CN104203939B - As human respiratory syncytial virus（RSV）The di-amino-pyrimidine of inhibitor - Google Patents

As human respiratory syncytial virus（RSV）The di-amino-pyrimidine of inhibitor Download PDF

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CN104203939B
CN104203939B CN201380020271.7A CN201380020271A CN104203939B CN 104203939 B CN104203939 B CN 104203939B CN 201380020271 A CN201380020271 A CN 201380020271A CN 104203939 B CN104203939 B CN 104203939B
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pyrimidine
dimethyl
diamines
pyridine
ylmethyls
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CN104203939A (en
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T.德赫特亚
A.贡茨彦
M-A.莫拉
A.瓦苏德文
吴 T.(I.C.)
M.沙菲夫
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AbbVie Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

This disclosure relates to：（a）Compound and its salt, it especially suppresses rsv infection and/or duplication；（b）Intermediate for preparing such compound and salt；（c）Composition comprising such compound and salt；（d）The method for preparing such intermediate, compound, salt and composition；（e）Use the method for such compound, salt and composition；With（f）Kit comprising such compound, salt and composition.

Description

As human respiratory syncytial virus（RSV）The di-amino-pyrimidine of inhibitor
Technical field
This disclosure relates to：（a）Compound and its salt, its particularly for suppress human respiratory syncytial virus (RSV) infection and/ Or replicate；（b）Intermediate for preparing such compound and salt；（c）Composition comprising such compound and salt；（d）System The method of standby such intermediate, compound, salt and composition；（e）Use the method for such compound, salt and composition；With（f） Kit comprising such compound, salt and composition.
Background
Human respiratory syncytial virus（RSV）Be paramyxovirus section (Paramyxoviridae) Pneumovirinae in family.It It is tunicary, non-segmented negative, minus-stranded rna virus.Its 15.2 kb genomes have been sequenced completely and it contains coding 11 10 mRNA of individual different albumen.RSV has three for adhering to and entering required cross-film surface protein（F、G、SH）, two Non-structural protein（NS1、NS2）, a matrix（M）Albumen, one make the nucleocapsid of viral RNA genes group encapsidate（N）Albumen, One phosphoprotein（P）With a RNA polymerase（L）.Additionally, RSV M2 mRNA coding M2-1 and M2-2 albumen.
RSV is the main cause of serious ALRI in infants and young.The baby and children of major part infection Moderate symptoms are only suffered from, but there is the lower respiratory tract sign of indicator virus capillary bronchitis or pneumonia in their 25-40%.Sternly The lower respiratory tract rsv infection of weight can cause the consequence of the different orders of severity, scope to be raised till death from there is childhood asthma risk Die.After rsv infection, it is incomplete to be immunized, and subinfection again may occur in life.Estimate that RSV is annual in world's model Cause about 60,000,000 infection and 160,000 death in enclosing.Rsv infection causes annual up to 125,000 babies in the U.S. Hospitalization, its baby for being equal to the age group about 0.1-0.2% is admitted to hospital.It is mostly in the baby in the risk of severe RSV disease Youngster is the baby and the baby with bronchopulmonary dysplasia, congenital heart disease or immune deficiency of premature labor.With these diseases The proportion of being admitted to hospital of condition is for 5%-30%.The death rate is for about 3% for the children with the heart and lung disease in the children being admitted to hospital, And for the children without these risk factors up to 1%.During rsv infection is also the elderly and compromised immune crowd The major reason of the incidence of disease.In the elderly being admitted to hospital, the death rate can be up to 10-20%, and with the tight of RSV pneumonia In the compromised immune patient of weight, the ratio is for about 50%.
RSV epidemic diseases annual winter in temperate climate all occurs.There are two groups of RSV（Also referred to as subgroup）A and B. Group A and B can altogether be propagated in epidemic disease, but their relative scale every year may change.Main epidemic disease group also may be used Change with not the same year, wherein group A is somewhat higher as the incidence of main group.Sequence homology between two groups It is different in different virus proteins.For example, F and N protein are highly conserved, have 91% and 96% respectively in two groups Amino acid identities.On the other hand, the sequence of G-protein is significantly different between two groups, and amino acid identities are only 53%. There are the data of the contradiction on Virulence Difference between two groups of RSV.Some researchs are found in the disease caused by two groups Clinical severity aspect without difference, and other then report that crowd A seems related to more serious disease.
At present, in the absence of the vaccine clinically ratified or effective antiviral therapy for treating RSV.Open so far The trial for sending out RSV vaccines safe and efficient not yet succeeds, partially due to the individuality in risk（Including baby, always Year people and the people of compromised immune）Treatment-related challenge, the individuality is low generally for the side effect tolerance of vaccine And tend to producing the immune response for weakening due to their jejune or worse immune systems.
Ribavirin has been used for treating rsv infection, but needs long-term Aerosol administration, and to it in treatment RSV senses Security and effect in dye also leave a question open.Additionally, Ribavirin and undesirable side effect such as anaemia, fatigue, irritability, skin Rash, nasal obstruction, nasosinusitis, cough even inborn defect are relevant.
Palivizumab/Synagis®It is directed to the mouse monoclonal antibody of the humanization of RSV F proteins, it has been used for passively Immunoprophylaxis come prevent virus to lower respiratory tract propagation.Although palivizumab is successfully used in reduction High risk group The frequency of being admitted to hospital of rsv infection, but the antibody is approved only for the baby in the risk in there are serious symptoms from rsv infection （Such as premature, and/or the baby with the congenital heart or lung disease）In preventative purposes.
Accordingly, there exist the notable demand for such compound, the compound is used to prevent and treat rsv infection simultaneously For extending to the adult in the risk with acute rsv infection and children's safety and the therapy of effective treatment.
General introduction
Disclosed herein is formula（I）Compound, and the method for preparing such compound,
Wherein：
R1It is C1-C6- alkyl, C1-C6- haloalkyl, C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6- alkyl, phenyl, Aryl bicyclic, phenyl-C1-C6- alkyl, heterocyclic radical, heterocyclic radical-C1-C6- alkyl, bicyclic heteroaryl or bicyclic heteroaryl-C1- C6- alkyl；Wherein described C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl, heterocyclic radical and heterocycle Base-C1-C6The heterocyclic radical of-alkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- Alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, Hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkane Base ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N (Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a- CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N (Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a- N(Rb1)S(O)2Rb1And L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl, aryl bicyclic, phenyl-C1-C6The benzene of-alkyl Base, bicyclic heteroaryl and bicyclic heteroaryl-C1-C6The bicyclic heteroaryl of-alkyl is optionally taken by 1,2,3,4 or 5 selected from following Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON (Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S (O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O (Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1- CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra) (Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd L1-N(Rb)C(O)O(Rb)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1Be phenyl or bicyclic heteroaryl, wherein the phenyl or bicyclic heteroaryl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re) (Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N (Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O) Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、- L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd- L3-N(Rf)C(O)O(Rf)；
X is selected from O, S, NRgOr C (RhRi)；
RaHydrogen, C are each independently when occurring every time1-C6- alkyl, C1-C6- haloalkyl or C3-C8- cycloalkyl, Wherein described C3-C8- cycloalkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：Halogen, oxo, C1-C3Alkane Base and C1-C3- haloalkyl；
Ra1Hydrogen, C are each independently when occurring every time1-C6- alkyl, C1-C6- haloalkyl or C3-C8- cycloalkyl, Wherein described C3-C8- cycloalkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：Halogen, oxo, C1-C3Alkane Base and C1-C3- haloalkyl；
RbIt is each independently hydrogen, C1-C6- alkyl or C1-C6- haloalkyl；
Rb1It is each independently hydrogen, C1-C6- alkyl or C1-C6- haloalkyl；
ReHydrogen, C are each independently when occurring every time1-C6- alkyl, C1-C6- haloalkyl or C3-C8- cycloalkyl, Wherein described C3-C8- cycloalkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：Halogen, oxo, C1-C3Alkane Base and C1-C3- haloalkyl；
RfIt is each independently hydrogen, C1-C6- alkyl or C1-C6- haloalkyl；
RgIt is hydrogen or C1-C6- alkyl；
RhAnd RiIt independently is hydrogen, C1-C6- alkyl or C1-C6- haloalkyl；
L1C is each independently when occurring every time1-C6- alkylidene or C3-C8- cycloalkyl, wherein L1Each optionally by 1, 2nd, 3 or 4 halogens or 1 or 2 hydroxyl are replaced；
L1aC is each independently when occurring every time1-C6- alkylidene or C3-C8- cycloalkyl, wherein L1aRespective optionally quilt 1st, 2,3 or 4 halogens or 1 or 2 hydroxyl are replaced；And
L3C is each independently when occurring every time1-C6- alkylidene or C3-C8- cycloalkyl, wherein L3Each optionally by 1, 2nd, 3 or 4 halogens are replaced.
The disclosure further relates to one or more compound described herein comprising therapeutically effective amount or its can pharmaceutically be connect The salt of salt, solvate or the solvate received and combination has one or more drug regimen of pharmaceutically acceptable carrier Thing.
The disclosure further relates to compound and/or salt comprising one or more disclosure and optionally one or more another The composition of outer therapeutic agent（Including pharmaceutical composition）.
The disclosure further relates to compound and/or salt comprising one or more disclosure and optionally one or more another The kit of outer therapeutic agent.
The disclosure is further related to using the compound, salt, composition and/or kit for example for suppressing RNA virus（Bag Include RSV）Duplication method.
The disclosure further relates to prepare medicine using one or more compound and/or salt of the disclosure.The medicine is appointed Choosing can contain one or more other therapeutic agent.In some embodiments, the medicine is used to treat rsv infection.
The compound, the salt comprising the compound, its pharmaceutically acceptable salt, solvate or solvate Composition and treated by giving the compound or its composition or prevent the patient's condition and the method for illness is entered herein One step is described.These and other targets are further described in paragraphs below.These targets should not be considered as reducing the disclosure Scope.
Describe in detail
The detailed description be only intended to make disclosed embodiment familiar to the person skilled in the art, their principle and they Practical application so that those skilled in the art can change in their many forms and apply the embodiment party Case so that the need for they can be best suited for particular use.The purpose that this description and its specific embodiment are intended only to illustrate.Cause This, present disclosure is not limited to the embodiment described in present patent application, and can carry out various modifications.
The present disclosure describes formula（I）Compound and the method for preparing such compound,
Wherein R1、R2、R3、R4、R5、R6、G1With X as defined herein.Also disclose the composition comprising such compound and Use such compound and the method for the composition treatment patient's condition and illness.
In various embodiments, compound described herein can be with comprising variable, and it is in any substitution base or in institute Occur more than once in the compound of description or herein in any other formula.Definition of the variable when occurring every time independently of its Definition when occurring for another time.Additionally, the combination of variable is only just allowed when such combination produces the compound of stabilization.Surely Fixed compound is the compound that from reactant mixture can separate.
Definition
Term " alkenyl " represents the straight or branched hydrocarbon chain containing at least one carbon-to-carbon double bond.Term " C2-C10- alkenyl " Expression contains the 2-10 alkenyl of carbon atom.The non-limiting examples of alkenyl include butyl- 2,3- dialkylenes, vinyl, 2- propylene Base, 2- methyl -2- acrylic, 3- cyclobutenyls, 4- pentenyls, 5- hexenyls, 2- heptenyls, 2- methyl isophthalic acids-heptenyl and the 3- last of the ten Heavenly stems Alkenyl.
Term " alkenylene (alkenylene) " represent the divalent group derived from straight or branched hydrocarbon and contain at least one Individual carbon-to-carbon double bond.“C2-C6- alkenylene " is represented and contains the 2-6 alkenylene of carbon atom.The representative example of alkenylene include but It is not limited to-C (=CH2)-,-CH=CH- and-CH2CH=CH-。
" alkyl " represents straight or branched, saturation hydrocarbon chain as the term is employed herein.Such as " C1-C10- alkyl " table Show and contain 1-10 straight or branched, the saturated hydrocarbons of carbon atom.Such as " C1-C3- alkyl " is represented containing 1-3 carbon atom Straight or branched, saturated hydrocarbons.The example of alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, Zhong Ding Base, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyls, 2,2- dimethyl amyl groups, 2,3- bis- Methyl amyl, n-heptyl, n-octyl, n-nonyl and positive decyl.
Term " alkylidene " represents the divalent group derived from straight or branched, saturated hydrocarbon chain.The example of alkylidene includes But it is not limited to-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH(CH3)-and-CH2CH(CH3)CH2-。
Term " alkynyl " represents the straight or branched alkyl containing at least one carbon-to-carbon triple bond.Term " C2-C10- alkynyl " Expression contains the 2-10 alkynyl of carbon atom.The representative example of alkynyl includes but is not limited to acetenyl, 1- propinyls, 2- propine Base, 3- butynyls, valerylene base and 1- butynyls.
" aryl " represents phenyl or aryl bicyclic as the term is employed herein.Such as " C6-C10- aryl " refers to can have 6- 10 aryl of carbon atom.Aryl bicyclic is naphthyl or the phenyl that is condensed with monocyclic cycloalkyl or is condensed with monocyclic cycloalkenyl Phenyl.The non-limiting examples of aryl include dihydro indenyl, indenyl, naphthyl, ihydro naphthyl and tetralyl.Aryl can be not It is substitution or substituted, and aryl bicyclic is connected to parent molecule through any commutable carbon atom that second cycle line system is contained within Part.
" aryl alkyl " refers to the aryl that parent molecular moiety is connected to through alkyl as the term is employed herein.
Term " cyano group " expression-CN, it can also be described as-C ≡ N.
" cycloalkenyl group " or " cyclenes " represents monocyclic or bicyclic hydrocarbons loop systems as the term is employed herein.Monocyclic cycloalkenyl has 4,5,6,7 or 8 carbon atoms and 0 hetero atom.Quaternary loop systems have a double bond, five or hexa-atomic loop systems tool Have one or two double bond, and seven or octatomic ring system there is one, two or three double bond.The representativeness of monocyclic cycloalkenyl Example includes but is not limited to cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl and cyclo-octene base.Bicyclic cycloalkenyl be with Monocyclic cycloalkenyl that monocyclic cycloalkyl is condensed or the monocyclic cycloalkenyl condensed with monocyclic cycloalkenyl.Monocyclic or bicyclic cycloalkenyl ring One or two alkylidene bridge can be contained, each is made up of one, two or three carbon atom, each connects loop systems Two non-conterminous carbon atoms.The representative example of bicyclic cycloalkenyl includes but is not limited to 4,5,6,7- tetrahydrochysenes -3aH- indenes, eight Hydrogen naphthyl and 1,6- dihydros-pentalene.Monocyclic and bicyclic cycloalkenyl can be may replace with included any in loop systems Atom be connected to parent molecular moiety, and can be unsubstituted or substituted.
" cycloalkyl " or " cycloalkanes " represents monocyclic, two rings or three rings cycloalkyl as the term is employed herein.It is monocyclic Cycloalkyl is to contain 3-8 carbon atom, 0 hetero atom and 0 carbocyclic ring system system of double bond.The example of monocyclic ring systems includes ring Propyl group, cyclobutyl, cyclopenta, cyclohexyl, suberyl and cyclooctyl.Bicyclic cycloalkyl is the list for being fused to monocyclic cycloalkyl ring Ring cycloalkyl.Tricyclic naphthenes base is as exemplified by the bicyclic cycloalkyl for being fused to monocyclic cycloalkyl.Monocyclic or bicyclic cycloalkyl ring can So that containing one or two alkylidene bridge, each is made up of 1,2 or 3 carbon atoms, respective not phase of connection two of loop systems Adjacent carbon atom.The non-limiting examples of such bridged ring alkyl loop systems include two rings [3.1.1] heptane, two rings [2.2.1] heptane, two rings [2.2.2] octane, two rings [3.2.2] nonane, two rings [3.3.1] nonane, two rings [4.2.1] nonane, Three ring [3.3.1.03,7] nonane (octahydro -2,5- endo-methylene groups pentalene or drop adamantane) and three ring [3.3.1.13,7] Decane (adamantane).Monocyclic, two rings and tricyclic naphthenes base can be unsubstituted or substituted, and included in loop systems Any commutable atom be connected to parent molecular moiety.
" cycloalkyl-alkyl " refers to the cycloalkyl that parent molecular moiety is connected to through alkyl as the term is employed herein.
" halo (halo) " or " halogen (halogen) " represents Cl, Br, I or F as the term is employed herein.
" haloalkyl " represents alkyl as defined herein as the term is employed herein, wherein 1,2,3,4,5 or 6 hydrogen originals Son is substituted by halogen.Term " C1-C10- haloalkyl " represents C as defined herein1-C10Alkyl, wherein 1,2,3,4,5 or 6 hydrogen atoms are substituted by halogen.The representative example of haloalkyl includes but is not limited to chloromethyl, 2- fluoro ethyls, 2,2,2- The chloro- 3- fluorine amyl groups of trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl group, 2-, triRuorobutyl (such as, but not limited to 4,4, 4- triRuorobutyls) and trifluoro propyl (such as, but not limited to 3,3,3- trifluoro propyls).
" haloalkenyl group " refers to alkenyl as defined herein as the term is employed herein, and it is taken by 1,2,3 or 4 halogen atoms Generation.
" halo alkynyl " refers to alkynyl as defined herein as the term is employed herein, and it is taken by 1,2,3 or 4 halogen atoms Generation.
" heterocycle ", " heterocyclic radical " or " heterocycle " represents monocyclic heterocycles, bicyclic heterocycles or three rings as the term is employed herein Heterocycle.Monocyclic heterocycles be containing at least one independently selected from the heteroatomic ternary of O, N and S, quaternary, five yuan, it is hexa-atomic, seven yuan Or octatomic ring.Ternary or four-membered ring contain 0 or 1 double bond and a hetero atom selected from O, N and S.Five-membered ring contains 0 or 1 Double bond and 1,2 or 3 hetero atoms selected from O, N and S.Hexatomic ring contains 0,1 or 2 double bond and 1,2 or 3 are selected from O, N and S Hetero atom.Heptatomic ring and octatomic ring contain 0,1,2 or 3 double bonds and 1,2 or 3 hetero atoms selected from O, N and S.It is monocyclic The non-limiting examples of heterocycle include azetidinyl, nitrogen heterocyclic heptyl, '-aziridino, Diazesuberane base, 1,3- Dioxane hexyl, 1,3- dioxolyls, 1,3- dithias cyclopenta, 1,3- dithias cyclohexyl, imidazolinyl, imidazoles Alkyl, isothiazoline base（isothiazolinyl）, isothiazole alkyl (isothiazolidinyl), isoxazoline-3-yl （isoxazolinyl）, isoxazole alkyls（isoxazolidinyl）, morpholinyl, oxadiazole quinoline Ji, oxadiazole alkyl, oxazolines Base, oxazole alkyl, oxetanyl, piperazinyl, piperidyl, pyranose, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrroles Alkyl（Including but not limited to, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl）, tetrahydrofuran base（Including but do not limit In tetrahydrofuran -3- bases）, THP trtrahydropyranyl, tetrahydro-thienyl, Thiadiazoline base, thiadiazoles alkyl, thiazolinyl, thiazolidine Base, thio-morpholinyl, 1,1- titanium dioxide thio-morpholinyls（Thiomorpholine sulfone）, thiopyranyl and trithiane base.Bicyclic heterocycles For the monocyclic heterocycles for being fused to phenyl or the monocyclic heterocycles for being fused to monocyclic cycloalkyl or it is fused to the monocyclic of monocyclic cycloalkenyl Heterocycle is fused to the monocyclic heterocycles of monocyclic heterocycles.The non-limiting examples of bicyclic heterocycles include benzopyranyl, benzothiopyran derivative Base, 2,3- dihydro benzo furyls, 2,3- dihydrobenzos thienyl, benzo [d] [1,3] dioxa cyclopentenyl (dioxolyl), Chromanyl and 2,3- dihydro -1H- indyls.Tricyclic heterocyclic is by being fused to the bicyclic heterocycles of phenyl or being fused to The bicyclic heterocycles of monocyclic cycloalkyl are fused to the bicyclic heterocycles of monocyclic cycloalkenyl or are fused to the bicyclic heterocycles of monocyclic heterocycles It is exemplified.Monocyclic and bicyclic heterocycles can the alkenylene bridge containing 2,3 or 4 carbon atoms or one or two 1,2,3 or 4 The alkylidene bridge of carbon atom or its combination, each of which bridging connect two non-conterminous atoms of loop systems.Such bridging it is miscellaneous The non-limiting examples of ring include octahydro -2,5- epoxies pentalene, azabicyclic [2.2.1] heptyl (including 2- azepines two Ring [2.2.1] hept- 2- yls), hexahydro -2H- 2,5- endo-methylene groups cyclopenta [b] furans, hexahydro -1H- 1,4- endo-methylene groups Cyclopenta [c] furans, azepine-adamantane (1- aza-tricycles [3.3.1.13,7] decane) and oxa--adamantane (2- oxygen Miscellaneous three rings [3.3.1.13,7] decane).Monocyclic, two rings and tricyclic heterocyclic can be it is unsubstituted or substituted, and it is included in Any commutable carbon atom or any commutable nitrogen-atoms in ring are connected with parent molecular moiety.Nitrogen and sulphur in heterocycle Hetero atom can optionally be oxidized and nitrogen-atoms can optionally be quaternized.Term " N- heterocyclic radicals " refers to and is connected to through nitrogen-atoms The nitrogenous heterocyclic group of parent molecular moiety.
" cycloheteroalkylalkyl " refers to the heterocyclic radical that parent molecular moiety is connected to through alkyl as the term is employed herein.
" heteroaryl " represents bicyclic heteroaryl or bicyclic heteroaryl as the term is employed herein.Bicyclic heteroaryl be five yuan or Hexatomic ring.Five-membered ring contains two double bonds.Five-membered ring can be containing 1 hetero atom selected from O or S；Or 1,2,3 or 4 nitrogen originals Sub and optional 1 oxygen atom or 1 sulphur atom.Hexatomic ring contains three double bonds and 1,2,3 or 4 nitrogen-atoms.Bicyclic heteroaryl Representative example include but is not limited to furyl（Including but not limited to, furans -2- bases）, imidazole radicals（Including but not limited to, 1H- imidazoles -1- bases）, isoxazolyls, isothiazolyl, oxadiazolyls, 1,3- oxazolyls, pyridine radicals（Such as pyridin-4-yl, pyrrole Pyridine -2- bases, pyridin-3-yl）, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrazolyl, pyrrole radicals, tetrazole radical, thiadiazolyl group, 1,3- thiophenes Oxazolyl, thienyl（Including but not limited to, thiophene -2- bases, thiene-3-yl）, triazolyl and triazine radical.Bicyclic heteroaryl is by condensing To phenyl bicyclic heteroaryl or be fused to the bicyclic heteroaryl of monocyclic cycloalkyl or be fused to the monocyclic miscellaneous of monocyclic cycloalkenyl Aryl is fused to the bicyclic heteroaryl of bicyclic heteroaryl or is fused to the bicyclic heteroaryl composition of monocyclic heterocycles.Two ring heteroaryls The non-limiting examples of base include benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, Ben Bing oxadiazolyl, 6,7- dihydro -1,3- benzothiazolyls, furans simultaneously [3,2-c] pyridazinyl, furans simultaneously [3,2-d] pyrimidine radicals, furans simultaneously [2,3-b] Pyrazinyl, furans simultaneously [2,3-c] pyridazinyl, furans simultaneously [2,3-d] pyrimidine radicals, furans simultaneously [3,2-b] pyridine radicals, furans simultaneously [3, 2-c] pyridine radicals, furans simultaneously [2,3-c] pyridine radicals, furans simultaneously [2,3-b] pyridine, imidazo [2,1-b] oxazolyls, imidazo [1,2-a] pyridine radicals, imidazo [2,1-b] [1,3,4] thiadiazolyl group, imidazo [2,1-b] [1,3,4] thiadiazolyl group, imidazoles And [1,2-d] [1,2,4] thiadiazolyl group, imidazo [2,1-b] thiazolyl, indazolyl, indolizine base, indyl, isoindolyl, Isoquinolyl, naphthyridines base, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-c] pyrimidine radicals, pyrazolo [1,5-a] pyrimidine radicals, Pyrazolo [5,1-c] [1,2,4] triazine radical, pyridine-imidazole base, quinolyl, simultaneously [5,4-b] pyridine -2- bases, thiazole be simultaneously for thiazole [5,4-d] pyrimidine -2-base and 5,6,7,8- tetrahydroquinoline -5- bases.Monocyclic and bicyclic heteroaryl can be substitution or unsubstituted , and the included any commutable carbon atom in loop systems or any commutable nitrogen-atoms are connected to parent molecule Part.
" heteroaryl alkyl " refers to the heteroaryl that parent molecular moiety is connected to through alkyl as the term is employed herein.
" hetero atom " represents nitrogen, oxygen or sulphur atom as the term is employed herein.
Term " hydroxyl（hydroxyl）" or " hydroxyl（hydroxy）" represent-OH groups.
" bicyclic heteroaryl alkyl " refers to the monocyclic heteroaryl that parent molecular moiety is connected to through alkyl as the term is employed herein Base.
" oxo " expression=O groups as the term is employed herein.
" phenylalkyl " refers to the phenyl that parent molecular moiety is connected to through alkyl as the term is employed herein.
In some cases, hydrocarbyl substituent（Such as alkyl or cycloalkyl）In carbon atom number by prefix " Cx-Cy-” It is represented, wherein x be replace base in carbon number minimum value and y be maximum.Thus, for example, " C1-C6- alkyl " refer to containing The 1-6 alkyl substituent of carbon atom.Further illustrate, C3-C6- cycloalkanes basis representation contains the 3-6 hydrocarbon of the saturation of carboatomic ring atom Basic ring.
The carbon atom or nitrogen-atoms of at least one and one or more hydrogen atom bondings are included if instead of base, then it is " commutable ".Thus, for example, hydrogen, halogen and cyano group are without falling into this definition.Additionally, in the heterocyclic radical containing such atom Sulphur atom can be replaced by one or two oxo substituent.
It is described as " substituted " if instead of base, then the hydrogen-based on the carbon or nitrogen of non-hydrogen group vicarious substitute base.Therefore, For example, the alkyl substituent of substitution is the alkyl substitution of the hydrogen-based on the non-hydrogen group replacement alkyl substituent of wherein at least one Base.In order to illustrate, single fluoroalkyl is that, by fluorine-based substituted alkyl, and fluoroalkyl is by two fluorine-based substituted alkyl.Should This recognizes that, if there is more than one substitution on substitution base, each non-hydrogen group can be same or different （Unless otherwise indicated）.
It is described as " optionally substituted " if instead of base, then replaces base to be（1）It is unsubstituted or（2）Substitution. It is described as optionally by up to certain number of non-hydrogen substituent group if instead of base, then the substitution base can be（1）Do not take Generation；Or（2）By up to certain number of non-hydrogen group or the maximum number of position is may replace on up to substitution base（With less Person is defined）Replaced.Thus, for example, be described as optionally by up to 3 heteroaryls of non-hydrogen substituent group if instead of base, It is then any optionally to may replace position one by what is up to only had with the heteroaryl having less than 3 heteroaryls that may replace position Non- hydrogen group more than sample is replaced.In order to illustrate, tetrazole radical（It only has one and may replace position）It is optionally non-by up to one Hydrogen group replaces.In order to further illustrate, if ammonia nitrogen is described as optionally by up to 2 non-hydrogen substituent groups, primaquine Base nitrogen is optionally by up to 2 non-hydrogen substituent groups, and secondary amino nitrogen is optionally by up to only 1 non-hydrogen substituent group.
Present patent application is used interchangeably term " substitution base " and " group ".
Prefix " halo " represents that the substitution base for being connected with the prefix is replaced by one or more halogen groups for independently selecting. For example, haloalkyl represents the alkyl substituent that wherein at least one hydrogen group is substituted by halogen group.The reality of haloalkyl Example includes chloromethyl, 1- bromoethyls, methyl fluoride, difluoromethyl, trifluoromethyl and 1,1,1- trifluoroethyls.It should be appreciated that such as Fruit substitution base is replaced by more than one halogen group, then those halogen groups can be same or different（Unless otherwise Explanation）.
Prefix " perhalogeno " represents the halogen that each hydrogen group being connected with the substitution base of the prefix is independently selected Group is substituted, that is, replace each hydrogen group on base to be substituted by halogen group.It is identical if all of halogen group , then prefix will generally determine the halogen group.Thus, for example, term " perfluoro " represents the substitution base being connected with the prefix On each hydrogen group substituted by fluorin radical.In order to illustrate, term " perfluoroalkyl " represents that wherein fluorin radical is substituted The alkyl substituent of each hydrogen group.
The prefix being connected with multicomponent substitution base is only applicable to the first component.In order to illustrate, term " alkyl-cycloalkyl " contains There are two kinds of components：Alkyl and cycloalkyl.Therefore, C1-C6C on-alkyl-cycloalkyl1-C6- prefix represents the alkane of alkyl-cycloalkyl Base component contains 1-6 carbon atom；C1-C6- prefix does not describe cycloalkyl component.In order to further illustrate, halogenated alkoxy alkyl On prefix " halo " represent only alkoxyalkyl substituent alkoxy component replaced by one or more halogen groups.If Halogen substitution can be appeared in optionally or additionally in alkyl component, then replace base to be changed to be described as " the alcoxyl of halogen substitution Base alkyl " rather than " halogenated alkoxy alkyl ".And it is last, if halogen substitution may be only occurred in alkyl component, take Dai Ji will be changed to be described as " alkoxyhaloalkyl groups ".
It is described as " independently selected from " one group of group if instead of base, then each substitution base is selected independently of one another.Respectively take For gene, this can be identical or different with other substitution bases.
When word is used to describe substitution base, the component for replacing the rightmost description of base is the component with free valency.
When chemical formula is used to describe substitution base, the short-term on the left of formula represents the part of the substitution base with free valency.
When chemical formula be used for the chemical constitution is described two other elements between connection element when, substitution base it is most left The short-term on side represents the part of the substitution base being connected with the left element in the structure.On the other hand, the short-term table of rightmost Show the part of the substitution base being connected with the right side element of the structure.In order to illustrate, if the chemical constitution is W-L-Y and L Be described as-C (O)-N (H)-, then the chemical formula will be W-C (O)-N (H)-Y.
This document describes formula（I）Compound.
Formula（I）Compound in variable groups occurrence it is as follows.If be adapted to, can with it is any it is defined herein other Value, definitions, claims or embodiments are used together such value.
In certain embodiments, R1It is C1-C6- alkyl, C1-C6- haloalkyl, C3-C8- cycloalkyl, C3-C8- cycloalkanes Base-C1-C6- alkyl, phenyl, aryl bicyclic, phenyl-C1-C6- alkyl, heterocyclic radical, heterocyclic radical-C1-C6- alkyl, monocyclic heteroaryl Base or bicyclic heteroaryl-C1-C6- alkyl；Wherein described C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- Cycloalkyl, heterocyclic radical and heterocyclic radical-C1-C6The heterocyclic radical of-alkyl is optionally taken by 1,2,3 or 4 selected from following substitution base Generation：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo Alkynyl, halogen, oxo, cyano group, hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1- C3- alkylidene-O-C1-C6- alkyl ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C (O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1) (Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N (Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、- L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a- CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1) (Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl, two rings Aryl, phenyl-C1-C6The phenyl of-alkyl, bicyclic heteroaryl and bicyclic heteroaryl-C1-C6The bicyclic heteroaryl of-alkyl optionally quilt 1st, 2,3,4 or 5 are replaced selected from following substitution base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O- Rb、-CN、-N(Rb)C(O)Rb、-CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、- N(Rb)C(O)N(Rb)2、-S-Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N (Rb)C(O)O(Rb)、-N(Rb)S(O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、- L1-C(O)Rb、-L1-OC(O)Rb、-L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、- L1-S(O)Rb、-L1-SO2N(Ra)(Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Its Middle L1、L1a、Ra、Ra1、RbAnd Rb1Such as it is described herein.
In certain embodiments, R1It is C1-C6- alkyl or C1-C6- haloalkyl.
In certain embodiments, R1It is C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6- alkyl, phenyl, two cyclophanes Base, phenyl-C1-C6- alkyl, heterocyclic radical, heterocyclic radical-C1-C6- alkyl, bicyclic heteroaryl or bicyclic heteroaryl-C1-C6- alkyl； Wherein described C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl, heterocyclic radical and heterocyclic radical-C1- C6The heterocyclic radical of-alkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, hydroxyl ,- O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkyl ,-C1- C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O) Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N (Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C (O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1) (Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S- Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl, aryl bicyclic, phenyl-C1-C6The phenyl of-alkyl, monocyclic heteroaryl Base and bicyclic heteroaryl-C1-C6The bicyclic heteroaryl of-alkyl is optionally replaced by 1,2,3,4 or 5 selected from following substitution base： Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON(Ra)(Rb)、-C(O) Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S(O)2Rb、-S(O) Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O(Rb)、-L1-O- Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1-CO2H、-L1- CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra)(Rb)、-L1-N (Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Wherein L1、L1a、Ra、Ra1、RbAnd Rb1Such as it is described herein.
In certain embodiments, R1It is C3-C8- cycloalkyl, phenyl, aryl bicyclic, heterocyclic radical or bicyclic heteroaryl；Its Described in C3-C8- cycloalkyl and heterocyclic radical are optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, Cyano group, hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1- C6- alkyl ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,- N(Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N (Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a- CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N (Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a- N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl, aryl bicyclic and bicyclic heteroaryl optionally by 1, 2nd, 3,4 or 5 are replaced selected from following substitution base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、- CN、-N(Rb)C(O)Rb、-CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N (Rb)C(O)N(Rb)2、-S-Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N (Rb)C(O)O(Rb)、-N(Rb)S(O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、- L1-C(O)Rb、-L1-OC(O)Rb、-L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、- L1-S(O)Rb、-L1-SO2N(Ra)(Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Its Middle L1、L1a、Ra、Ra1、RbAnd Rb1Such as it is described herein.
In certain embodiments, R1It is C3-C8- cycloalkyl or heterocyclic radical；Wherein described C3-C8- cycloalkyl and heterocyclic radical Optionally replaced selected from following substitution base by 1,2,3 or 4：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1- C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, hydroxyl ,-O-C1-C6- alkyl ,- O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkyl ,-C1-C3- alkylidene-O-C1- C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1) (Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N(Rb1)2、-S- Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O (Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1)(Rb1)、- L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S-Rb1、-L1a- S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N (Rb1)C(O)O(Rb1)；Wherein L1a、Ra1And Rb1Such as it is described herein.
In certain embodiments, R1It is selected from following C3-C8- cycloalkyl：Cyclobutane, pentamethylene, hexamethylene, cycloheptyl Alkane and norborny（norbornyl）；Wherein described C3-C8- cycloalkyl is optionally selected from following substitution base institute by 1,2,3 or 4 Substitution：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halogen For alkynyl, halogen, oxo, cyano group, hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,- C1-C3- alkylidene-O-C1-C6- alkyl ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、- C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1) (Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N (Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、- L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a- CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1) (Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein L1a、Ra1And Rb1Such as It is described herein.
In certain embodiments, R1It is selected from following C3-C8- cycloalkyl：Cyclobutane, pentamethylene, hexamethylene, cycloheptyl Alkane and norborny（norbornyl）；Wherein described C3-C8- cycloalkyl is optionally selected from following substitution base institute by 1,2,3 or 4 Substitution：Halogen, hydroxyl, hydroxymethyl, methyl and trifluoromethyl.
In certain embodiments, R1It is selected from following heterocyclic radical：Tetrahydrochysene -2H- pyrans -4- bases, 3,4- dihydros -2H- Chromene -4- bases, thiophane -3- bases and piperidin-4-yl；Wherein described heterocyclic radical is optionally taken by 1,2,3 or 4 selected from following Replaced for base：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2- C10- halo alkynyl, halogen, oxo, cyano group, hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene- O-H、-C1-C3- alkylidene-O-C1-C6- alkyl ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、- NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N (Ra1)(Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1) (Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、- L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、- L1a-CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1) (Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein L1a、Ra1And Rb1Such as It is described herein.
In certain embodiments, R1It is selected from following heterocyclic radical：Tetrahydrochysene -2H- pyrans -4- bases, 3,4- dihydros -2H- Chromene -4- bases, thiophane -3- bases and piperidin-4-yl；Wherein described heterocyclic radical is optionally by 1,2 or 3 or 4 selected from following Substitution base is replaced：Oxo, methyl and-C (O) O-C1-C6- alkyl.
In certain embodiments, R1It is phenyl, aryl bicyclic or bicyclic heteroaryl；Wherein described phenyl, two cyclophanes Base and bicyclic heteroaryl are optionally replaced by 1,2,3,4 or 5 selected from following substitution base：Halogen, C1-C6- alkyl, C1-C6- Haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N (Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra) (Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O) Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、- L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra)(Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd- L1-N(Rb)C(O)O(Rb)；Wherein L1、RaAnd RbSuch as it is described herein.
In certain embodiments, R1It is phenyl；Wherein described phenyl is optionally taken by 1,2,3,4 or 5 selected from following Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON (Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S (O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O (Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1- CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra) (Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Wherein L1、RaAnd RbSuch as it is described herein.
In certain embodiments, R1It is phenyl；Wherein described phenyl is optionally taken by 1,2,3,4 or 5 selected from following Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb；Wherein RbAs described in general introduction.
In certain embodiments, R1It is selected from following aryl bicyclic：2,3- dihydros -1H- indenes -1- bases, 1,2,3,4- Naphthane -1- bases and 2,3- dihydros -1H- indenes -2- bases；Wherein described aryl bicyclic is optionally by 1,2,3,4 or 5 selected from following Substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、- CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S- Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S (O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、- L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra) (Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Wherein L1、RaAnd RbSuch as it is described herein.
In certain embodiments, R1It is selected from following aryl bicyclic：2,3- dihydros -1H- indenes -1- bases, 1,2,3,4- Naphthane -1- bases and 2,3- dihydros -1H- indenes -2- bases.
In certain embodiments, R1It is bicyclic heteroaryl；Wherein described bicyclic heteroaryl is optionally by 1,2,3 or 4 choosings Replaced from following substitution base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C (O)Rb、-CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N (Rb)2、-S-Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O (Rb)、-N(Rb)S(O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、- L1-OC(O)Rb、-L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、- L1-SO2N(Ra)(Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Wherein L1、RaAnd Rb Such as it is described herein.
In certain embodiments, R1It is bicyclic heteroaryl；Wherein described bicyclic heteroaryl is selected from optionally by 1,2 or 3 Methyl substituted pyrazolyl, pyridine radicals, thiadiazolyl group, He isoxazolyl.
In certain embodiments, R1It is C3-C8- cycloalkyl-C1-C6- alkyl, phenyl-C1-C6- alkyl, heterocyclic radical-C1- C6- alkyl or bicyclic heteroaryl-C1-C6- alkyl；Wherein described C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl and Heterocyclic radical-C1-C6The heterocyclic radical of-alkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2- C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyanogen Base, hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- Alkyl ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N (Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a- CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N (Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a- N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl-C1-C6- phenyl and bicyclic heteroaryl of alkyl- C1-C6The bicyclic heteroaryl of-alkyl is optionally replaced by 1,2,3,4 or 5 selected from following substitution base：Halogen, C1-C6- alkane Base, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、- OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra) (Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O(Rb)、-L1-O-Rb、-L1-CN、- L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C (O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra)(Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S (O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Wherein L1、L1a、Ra、Ra1、RbAnd Rb1Such as it is described herein.
In certain embodiments, R1It is C3-C8- cycloalkyl-C1-C6- alkyl or heterocyclic radical-C1-C6- alkyl；Wherein institute State C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl and heterocyclic radical-C1-C6The heterocyclic radical of-alkyl is optionally by 1,2,3 or 4 It is individual to be replaced selected from following substitution base：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2- C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- alkyl halide Base ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkyl ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,- C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC (O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O) Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O (Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O) Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O) Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)； Wherein L1a、Ra1And Rb1Such as it is described herein.
In certain embodiments, R1It is C3-C8- cycloalkyl-C1-C6- alkyl or heterocyclic radical-C1-C6- alkyl；Wherein institute State C3-C8- cycloalkyl-C1-C6- alkyl and heterocyclic radical-C1-C6- alkyl is selected from cyclopentyl-methyl, cyclohexyl methyl and tetrahydrofuran Ylmethyl.
In certain embodiments, R1It is phenyl-C1-C6- alkyl or bicyclic heteroaryl-C1-C6- alkyl；Wherein described benzene Base-C1-C6The phenyl and bicyclic heteroaryl-C of-alkyl1-C6The bicyclic heteroaryl of-alkyl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、- CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S- Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S (O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、- L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra) (Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；Wherein L1、RaAnd RbSuch as it is described herein.
In certain embodiments, R1It is phenyl-C1-C6- alkyl；Wherein described phenyl-C1-C6- alkyl is benzyl；Wherein Phenyl-the C1-C6The phenyl of-alkyl is optionally by halogen or C1-C6- alkyl is replaced.
In certain embodiments, R2It is methyl or ethyl.
In certain embodiments, R2It is methyl.
In certain embodiments, R2It is ethyl.
In certain embodiments, R3It is methyl or ethyl.
In certain embodiments, R3It is methyl.
In certain embodiments, R3It is ethyl.
In certain embodiments, R2It is methyl and R3It is methyl.
In certain embodiments, R2It is methyl and R3It is ethyl.
In certain embodiments, R2It is ethyl and R3It is methyl.
In certain embodiments, R2It is ethyl and R3It is ethyl.
In certain embodiments, R4And R5Independently selected from hydrogen, C1-C6- alkyl or C1-C6- haloalkyl.
In certain embodiments, R4And R5Respectively hydrogen.
In certain embodiments, R4And R5Independently selected from C1-C6- alkyl or C1-C6- haloalkyl.
In certain embodiments, R4It is hydrogen and R5Selected from C1-C6- alkyl or C1-C6- haloalkyl.
In certain embodiments, R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl.
In certain embodiments, R6It is hydrogen.
In certain embodiments, R6It is C1-C6- alkyl.
In certain embodiments, R6It is C1-C6- haloalkyl.
In certain embodiments, G1It is phenyl or bicyclic heteroaryl, wherein the phenyl or bicyclic heteroaryl optionally quilt 1st, 2,3,4 or 5 are replaced selected from following substitution base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N (Rf)C(O)Rf、-CON(Re)(Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S (O)2Rf、-S(O)Rf、-SO2N(Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、- L3-CN、-L3-N(Rf)C(O)Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、- L3-N(Rf)C(O)N(Rf)2、-L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、- L3-N(Rf)S(O)2RfAnd-L3-N(Rf)C(O)O(Rf)；Wherein L3、ReAnd RfSuch as it is described herein.
In certain embodiments, G1For phenyl, wherein described phenyl optionally taken selected from following by 1,2,3,4 or 5 Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re)(Rf)、-C (O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N(Re) (Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O)Rf、-L3- CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、-L3-S- Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd-L3-N (Rf)C(O)O(Rf)；Wherein L3、ReAnd RfSuch as it is described herein.
In certain embodiments, G1For phenyl, wherein described phenyl optionally taken selected from following by 1,2,3,4 or 5 Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl or-O-Rf；Wherein RfIt is as described in general introduction.
In certain embodiments, G1It is bicyclic heteroaryl, wherein the bicyclic heteroaryl is optionally by 1,2,3,4 or 5 Replaced selected from following substitution base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、- CON(Re)(Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O) Rf、-SO2N(Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N (Rf)C(O)Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O) N(Rf)2、-L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S (O)2RfAnd-L3-N(Rf)C(O)O(Rf)；Wherein L3、ReAnd RfSuch as it is described herein.
In certain embodiments, G1It is bicyclic heteroaryl；Wherein described bicyclic heteroaryl be selected from pyridine radicals, pyrazolyl, Imidazole radicals, isoxazolyls and thienyl；Wherein described bicyclic heteroaryl is optionally selected from following substitution base institute by 1,2,3 or 4 Substitution：Halogen, C1-C6- alkyl, C1-C6- haloalkyl or-O-Rf；Wherein RfIt is as described in general introduction.
In certain embodiments, X is selected from O, S, NRgOr C (RhRi)。
In certain embodiments, X is O or S.
In certain embodiments, X is NRg；Wherein RgIt is hydrogen or C1-C6- alkyl.
In certain embodiments, X is NRg；Wherein RgIt is hydrogen.
In certain embodiments, X is NRg；Wherein RgIt is C1-C6- alkyl.
In certain embodiments, X is C (RhRi)；Wherein RhAnd RiIt independently is hydrogen, C1-C6- alkyl or C1-C6- halo Alkyl.
In certain embodiments, X is C (RhRi)；Wherein RhAnd RiRespectively hydrogen.
In certain embodiments, X is C (RhRi)；Wherein RhIt is hydrogen and RiIt is C1-C6- alkyl or C1-C6- haloalkyl.
In certain embodiments, X is C (RhRi)；Wherein RhC independently is with Ri1-C6- alkyl or C1-C6- alkyl halide Base.
It is formula in an aspect of this disclosure（I）Compound, wherein：
R1It is C1-C6- alkyl, C1-C6- haloalkyl, C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6- alkyl, phenyl, Aryl bicyclic, phenyl-C1-C6- alkyl, heterocyclic radical, heterocyclic radical-C1-C6- alkyl, bicyclic heteroaryl or bicyclic heteroaryl-C1- C6- alkyl；Wherein described C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl, heterocyclic radical and heterocycle Base-C1-C6The heterocyclic radical of-alkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- Alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, Hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkane Base ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N (Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a- CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N (Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a- N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl, aryl bicyclic, phenyl-C1-C6The benzene of-alkyl Base, bicyclic heteroaryl and bicyclic heteroaryl-C1-C6The bicyclic heteroaryl of-alkyl is optionally taken by 1,2,3,4 or 5 selected from following Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON (Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S (O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O (Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1- CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra) (Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1Be phenyl or bicyclic heteroaryl, wherein the phenyl or bicyclic heteroaryl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re) (Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N (Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O) Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、- L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd- L3-N(Rf)C(O)O(Rf)；With
X is selected from O or S；Wherein
L1、L1a、L3、Ra、Ra1、Rb、Rb1、ReAnd RfSuch as it is described herein.
It is formula in an aspect of this disclosure（I）Compound, wherein：
R1It is C1-C6- alkyl, C1-C6- haloalkyl, C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6- alkyl, phenyl, Aryl bicyclic, phenyl-C1-C6- alkyl, heterocyclic radical, heterocyclic radical-C1-C6- alkyl, bicyclic heteroaryl or bicyclic heteroaryl-C1- C6- alkyl；Wherein described C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl, heterocyclic radical and heterocycle Base-C1-C6The heterocyclic radical of-alkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- Alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, Hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkane Base ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N (Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a- CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N (Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a- N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl, aryl bicyclic, phenyl-C1-C6The benzene of-alkyl Base, bicyclic heteroaryl and bicyclic heteroaryl-C1-C6The bicyclic heteroaryl of-alkyl is optionally taken by 1,2,3,4 or 5 selected from following Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON (Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S (O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O (Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1- CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra) (Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1For phenyl or bicyclic heteroaryl, wherein described phenyl or bicyclic heteroaryl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re) (Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N (Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O) Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、- L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd- L3-N(Rf)C(O)O(Rf)；With
X is C (RhRi)；Wherein
L1、L1a、L3、Ra、Ra1、Rb、Rb1、Re、Rf、RhAnd RiSuch as it is described herein.
It is formula in an aspect of this disclosure（I）Compound, wherein：
R1It is C1-C6- alkyl, C1-C6- haloalkyl, C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6- alkyl, phenyl, Aryl bicyclic, phenyl-C1-C6- alkyl, heterocyclic radical, heterocyclic radical-C1-C6- alkyl, bicyclic heteroaryl or bicyclic heteroaryl-C1- C6- alkyl；Wherein described C3-C8- cycloalkyl, C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl, heterocyclic radical and heterocycle Base-C1-C6The heterocyclic radical of-alkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- Alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, Hydroxyl ,-O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkane Base ,-C1-C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N (Rb1)C(O)N(Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a- CON(Ra1)(Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N (Rb1)2、-L1a-S-Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a- N(Rb1)S(O)2Rb1And-L1a-N(Rb1)C(O)O(Rb1)；Wherein described phenyl, aryl bicyclic, phenyl-C1-C6The benzene of-alkyl Base, bicyclic heteroaryl and bicyclic heteroaryl-C1-C6The bicyclic heteroaryl of-alkyl is optionally taken by 1,2,3,4 or 5 selected from following Replaced for base：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON (Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S (O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O (Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1- CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra) (Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1For phenyl or bicyclic heteroaryl, wherein described phenyl or bicyclic heteroaryl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re) (Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N (Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O) Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、- L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd- L3-N(Rf)C(O)O(Rf)；With
X is NRg；Wherein
L1、L1a、L3、Ra、Ra1、Rb、Rb1、Re、RfAnd RgSuch as it is described herein.
In a specific subgroup, the disclosure characterizes formula（I）Compound, wherein
R1It is C1-C6- alkyl, C1-C6- haloalkyl, C3-C8- cycloalkyl or heterocyclic radical；Wherein described C3-C8- cycloalkyl Optionally replaced selected from following substitution base by 1,2,3 or 4 with heterocyclic radical：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynes Base, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, hydroxyl ,-O-C1-C6- Alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkyl ,-C1-C3- alkylene Base-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON (Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N(Rb1)2、- S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O (Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1)(Rb1)、- L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S-Rb1、-L1a- S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N (Rb1)C(O)O(Rb1)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1Be phenyl or bicyclic heteroaryl, wherein the phenyl or bicyclic heteroaryl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re) (Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N (Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O) Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、- L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd- L3-N(Rf)C(O)O(Rf)；With
X is NRg；Wherein
L1a、L3、Ra1、Rb1、Re、RfAnd RgSuch as it is described herein.
In a specific subgroup, the disclosure characterizes formula（I）Compound, wherein
R1It is phenyl, aryl bicyclic or bicyclic heteroaryl；Wherein described phenyl, aryl bicyclic and bicyclic heteroaryl are optional Replaced selected from following substitution base by 1,2,3,4 or 5：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-OCH2O-、-O- Rb、-CN、-N(Rb)C(O)Rb、-CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、-CO2H、-CO2Rb、- N(Rb)C(O)N(Rb)2、-S-Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N(Rb)S(O)2Rb、-N (Rb)C(O)O(Rb)、-N(Rb)S(O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1-CON(Ra)(Rb)、- L1-C(O)Rb、-L1-OC(O)Rb、-L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S-Rb、-L1-S(O)2Rb、- L1-S(O)Rb、-L1-SO2N(Ra)(Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N(Rb)C(O)O(Rb)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1For phenyl or bicyclic heteroaryl, wherein described phenyl or bicyclic heteroaryl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re) (Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N (Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O) Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、- L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd- L3-N(Rf)C(O)O(Rf)；With
X is NRg；Wherein
L1、L3、Ra、Rb、Re、RfAnd RgSuch as it is described herein.
In another specific subgroup, the disclosure characterizes formula（I）Compound, wherein
R1It is C3-C8- cycloalkyl-C1-C6- alkyl, phenyl-C1-C6- alkyl, heterocyclic radical-C1-C6- alkyl or monocyclic heteroaryl Base-C1-C6- alkyl；Wherein described C3-C8- cycloalkyl-C1-C6The C of-alkyl3-C8- cycloalkyl and heterocyclic radical-C1-C6- alkyl Heterocyclic radical is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynes Base, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, hydroxyl ,-O-C1-C6- Alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkyl ,-C1-C3- alkylene Base-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O)Rb1、-CON (Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N(Rb1)2、- S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C(O)O (Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1)(Rb1)、- L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S-Rb1、-L1a- S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1And-L1a-N (Rb1)C(O)O(Rb1)；Wherein described phenyl-C1-C6The phenyl and bicyclic heteroaryl-C of-alkyl1-C6The bicyclic heteroaryl of-alkyl Optionally replaced selected from following substitution base by 1,2,3,4 or 5：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,- OCH2O-、-O-Rb、-CN、-N(Rb)C(O)Rb、-CON(Ra)(Rb)、-C(O)Rb、-OC(O)Rb、-OS(O)2N(Ra)(Rb)、- CO2H、-CO2Rb、-N(Rb)C(O)N(Rb)2、-S-Rb、-S(O)2Rb、-S(O)Rb、-SO2N(Ra)(Rb)、-N(Ra)(Rb)、-N (Rb)S(O)2Rb、-N(Rb)C(O)O(Rb)、-N(Rb)S(O)2O(Rb)、-L1-O-Rb、-L1-CN、-L1-N(Rb)C(O)Rb、-L1- CON(Ra)(Rb)、-L1-C(O)Rb、-L1-OC(O)Rb、-L1-CO2H、-L1-CO2Rb、-L1-N(Rb)C(O)N(Rb)2、-L1-S- Rb、-L1-S(O)2Rb、-L1-S(O)Rb、-L1-SO2N(Ra)(Rb)、-L1-N(Ra)(Rb)、-L1-N(Rb)S(O)2RbAnd-L1-N (Rb)C(O)O(Rb)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1Be phenyl or bicyclic heteroaryl, wherein the phenyl or bicyclic heteroaryl optionally by 1,2,3,4 or 5 be selected from Under substitution base replaced：Halogen, C1-C6- alkyl, C1-C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re) (Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N(Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N (Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N(Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O) Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O)Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、- L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N(Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfAnd- L3-N(Rf)C(O)O(Rf)；With
X is NRg；Wherein
L1、L1a、L3、Ra、Ra1、Rb、Rb1、Re、RfAnd RgSuch as it is described herein.
In certain embodiments, R1Selected from phenyl, cyclohexyl, cyclopenta, suberyl, cyclobutyl, norborny （norbornyl）, indanyl, benzodioxole base, pyridine radicals, pyrazolyl, morpholinyl, thiadiazolyl group, thiophane Base, piperidyl He isoxazolyl.
In certain embodiments, R1Selected from phenyl and cyclohexyl.
In certain embodiments, G1Selected from phenyl, pyridine radicals, imidazole radicals, pyrazolyl He isoxazolyl.
In certain embodiments, G1Selected from phenyl and pyridine radicals.
In certain embodiments, R1It is cyclohexyl and G1It is pyridine radicals.
In certain embodiments, R1It is phenyl and G1It is pyridine radicals.
In certain embodiments, R1It is optionally substituted cyclohexyl；R2And R3Respectively methyl；R4、R5And R6Respectively Hydrogen；X is NRg, wherein RgIt is hydrogen；And G1It is optionally substituted pyridine radicals.
In certain embodiments, R1It is optionally substituted phenyl；R2And R3Respectively methyl；R4、R5And R6Respectively hydrogen； X is NRg, wherein RgIt is hydrogen；And G1It is optionally substituted pyridine radicals.
Exemplary compound is included but is not limited to：
N 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2- methyl-benzyls)-N 2- (pyridine -2- ylmethyls) -6,7- dihydros -5H- cyclopenta [d] pyrimidine -2,4- Diamines；
N 4- suberyl -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- cyclohexyl -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 2- benzyl-N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- (pyridin-3-yl methyl) pyrimidine -2,4- diamines；
2- ({ [4- (Cyclohexylamino) -5,6- dimethyl pyrimidine -2- bases] amino } methyl) -6- picoline -3- alcohol；
N 4- cyclohexyl-N 2- (4- methoxy-benzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (4- luorobenzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [4- (trifluoromethoxy) benzyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (4- isopropyl benzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [4- (trifluoromethyl) benzyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (3- luorobenzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2-(1H- pyrazoles -5- ylmethyls) pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2-[(1R) -1- phenylethyls] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2-[(1S) -1- phenylethyls] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(4- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- [(4-methoxypyridine -2- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(6- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- { [5- (trifluoromethyl) pyridine -2- bases] methyl } pyrimidine -2,4- diamines；
N 2- [(4- tert .-butylpyridine -2- bases) methyl] -N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- (2- thienyl methyls) pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- [(3,5- dimethyl -1,2- oxazole -4- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(1- methyl isophthalic acidsH- imidazol-4 yl) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (3- methoxy-benzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(3- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 2- [(4- chloropyridine -2- bases) methyl] -N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- [(4- picoline -2- bases) methyl] pyrimidine -2,4- two Amine；
N 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (tetrahydrochysene -2H- pyrans -4- bases) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethyl) cyclohexyl] pyrimidine -2,4- diamines；
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,3- dihydros -1H- indenes -1- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
3- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclopentanol；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (1,2,3,4- naphthane -1- bases) pyrimidine -2,4- diamines；
N 4- (3,4- dihydros -2H- chromene -4- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
Cis -4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) -1- methyl cyclohexanes Alcohol；
It is trans-4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) -1- methyl cyclohexanes Alcohol；
N 4- (two rings [2.2.1] hept- 2- yls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (2- methylcyclohexyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,3- Dimethylcyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
2- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol；
[(1R,2S) -2- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexyl] Methyl alcohol；
N 4- (cyclopentyl-methyl) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- suberyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,3- dihydros -1H- indenes -2- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- cyclobutyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (pentane -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (4- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- phenyl-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [3- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [3- (trifluoromethyl) phenyl] pyrimidine -2,4- diamines；
N 4- (2,6- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethyl) phenyl] pyrimidine -2,4- diamines；
N 4- (3,4- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [2- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines；
N 4- (2,5- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (1,3- benzodioxole -5- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- Diamines；
N 4- (4- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (4- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3,5- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (2- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,6- 3,5-dimethylphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (3- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (1,1- titanium dioxide thiophane -3- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- two Amine；
N 4- (5- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (the fluoro- 6- aminomethyl phenyls of 2-) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (the fluoro- 2- aminomethyl phenyls of 4,5- bis-) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (1- methyl isophthalic acidsH- pyrazoles -5- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (4- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 4, 5,6- trimethyls-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3,3- Difluorocyclopentyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
Trans -4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol；
N 4- (3,3- difiuorocyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (1- methyl piperidine -4- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) tertiary fourth of piperidines -1- formic acid Ester；
5,6- dimethyl-N 4- (piperidin-4-yl)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,6- diisopropyl phenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
3- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(5- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [1- (pyridine -2- bases) ethyl] pyrimidine -2,4- diamines；
N 4- (2,4 difluorobenzene base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5- ethyls-N 4- (4- fluorophenyls) -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (4,4- difiuorocyclohexyls)-N 2- [(4- ethylpyridine -2- bases) methyl] -5,6- dimethyl pyrimidines -2,4- two Amine；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (tetrahydrofuran -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (cyclohexyl methyl) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (pyridin-3-yl)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (1,3,4- thiadiazoles -2- bases) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (1,2- oxazole -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (5- methyl isophthalic acids, 2- oxazole -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines； Or
N 4- (4- luorobenzyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines.
Isomers
The disclosure considers various stereoisomers and its mixture, and these are expressly included in the scope of the present disclosure It is interior.Stereoisomer include enantiomter and diastereoisomer, and enantiomter or diastereoisomer mixing Thing.The various stereoisomers of the compound of the application can be from containing asymmetric or chiral centre commercially available starting material Matter is synthetically prepared or is then split by preparing racemic mixture（It is well known for those of ordinary skill in the art） To prepare.These method for splitting are by following come example：（1）The mixture of enantiomter is connected to chiral auxiliary, is passed through Recrystallization or the separating obtained diastereoisomer of chromatography mixture and optically pure product is discharged from auxiliary agent, or （2）The mixture of optical enantiomorphs is directly separated on chiral chromatographic column.
Geometric isomer may reside in disclosed compound.The disclosure is considered from carbon-to-carbon double bond, carbon-to-nitrogen double bond, ring Various geometric isomers and its mixture that the arrangement of alkyl or heterocyclic group peripheral substituents is obtained.Carbon-to-carbon double bond or carbon- The substitution base that substitution base around nitrogen key is named as around Z or E, and cycloalkyl or heterocycle is named as cis or trans structure Type.
It should be understood that compound disclosed herein there may be tautomerism.
Therefore, the formula figure in this specification can only represent one of possible tautomerism or stereoisomeric forms in any ratio.Ying Li The disclosed compound of solution includes any tautomerism or stereoisomeric forms in any ratio and its mixture, and should not be limited only to compound or Any tautomerism used or stereoisomeric forms in any ratio in the name of formula figure.
Isotope
The disclosure also compound including isotope marks, it is same with disclosed compound phase, except one or more are former Son substitutes this by the atom with the atomic mass or mass number different from the generally natural atomic mass for finding or mass number One is true.The example of the isotope being suitable including through in the compound of the disclosure be hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, it is all Such as, but not limited to, it is respectively2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl.It is all with heavier isotope As deuterium is2The substitution of H can provide some treatment benefits produced by more preferable metabolic stability, such as increased partly to decline in vivo Phase or the volume requirements of reduction, and therefore can use in some cases.The compound for mixing the isotope of transmitting positive electron can Positron emission computerized tomography for medical imaging and for determining acceptor distribution（PET）In research.Formula can be mixed（I）'s The isotope of the suitable transmitting positive electron in compound is11C、13N、15O and18F.The compound of the isotope marks of the disclosure Can generally be prepared by routine techniques well known by persons skilled in the art or by with the method described in appended embodiment Similar method is prepared using the reagent of suitable isotope marks instead of the reagent of nonisotopic labels.
Salt
The disclosure also relates in part to all salt of disclosed compound.Due to one or more characteristic of salt such as not Enhanced medicine stability or the desired solubility in water or other solvents under synthermal and humidity, the salt of compound may It is favourable.In the case where salt is intended to deliver medicine to patient（For example, with for opposite in external background）, salt can be pharmaceutically It is acceptable and/or physiologically compatible.Represented using term " pharmaceutically acceptable " with adjective in the disclosure The noun modified is suitable as medicine or the part as medicine.Pharmaceutically acceptable salt includes such as be commonly used for shape Into alkali metal salt or the salt of the addition salts for forming free acid or free alkali.Generally, these salt typically can be by conventional method example Such as react to prepare with disclosed compound through suitable acid or alkali.
The pharmaceutically acceptable acid-addition salts of the compound of the disclosure can be prepared from inorganic acid or organic acid.Properly Inorganic acid example include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Suitable organic acid is generally wrapped Include the organic acid of such as aliphatic series, cyclic aliphatic, aromatics, araliphatic, heterocycle, carboxylic acid and sulphonic acids.The specific reality of suitable organic acid Example includes acetic acid, trifluoroacetic acid, formic acid, propionic acid, butanedioic acid, glycolic, gluconic acid, didextrose acid, lactic acid, malic acid, winestone Acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, adjacent ammonia Yl benzoic acid, methanesulfonic acid, stearic acid, salicylic acid, P-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (embonate) （Pamoic acid (pamoate)）, ethyl sulfonic acid, benzene sulfonic acid, pantothenic acid, 2- ethylenehydrinsulfonic acids, sulfanilic acid, cyclohexylsulfamic, algae Acid, beta-hydroxy-butanoic acid, galactosaccharic acid, galacturonic acid, adipic acid, alginic acid, weight sulfuric acid, butyric acid, camphoric acid, camphorsulfonic acid, Pentamethylene propionic acid, dodecyl sulphate, sugared enanthic acid（glycoheptanoate）, phosphoglycerol, enanthic acid, caproic acid, nicotinic acid, oxalic acid, Palmitic acid, pectic acid（pectinate）, 2- naphthalene sulfonic acids, 3- phenylpropionic acids, picric acid, neopentanoic acid, thiocyanic acid, toluenesulfonic acid and Hendecanoic acid.
The pharmaceutically acceptable base addition salts of the compound of the disclosure include such as slaine and organic salt.Slaine can With including alkali metal（Race Ia）Salt, alkaline-earth metal（Race IIa）Salt and other physiologically acceptable slaines.Such salt can Prepared with from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc.Organic salt can be prepared from amine, such as trometamol, diethylamine,N,N'- Dibenzyl-ethylenediamin, chloroprocanine, choline, diethanol amine, ethylenediamine, meglumine（N-METHYL-ALPHA-L-GLUCOSAMINE）And procaine. The nitrogenous group of alkalescence can be quaternized with following reagent, such as low alkyl group（C1-C6）Halide（Such as methyl, ethyl, third The chloride of base and butyl, bromide and iodide）, dialkyl sulfate（For example, dimethyl suflfate, dithyl sulfate, sulfuric acid Dibutyl ester and diamyl sulfates）, long chain halide（For example, the chloride of decyl, lauryl, myristyl and stearyl, bromination Thing and iodide）, arylalkyl halide（For example, benzylic bromides and phenylethyl bromide）And other.
Purity
Purity with any level（Including pure and substantially pure）The disclosure compound（And its salt）At this In scope of disclosure." substantially pure " expression of term on compound/salt/isomers contains the compound/salt/isomery Preparation/the composition of body includes the compound/salt/isomers more than about 85 weight %, more than described in about 90 weight % Compound/salt/isomers, the compound/salt/isomers more than about 95 weight %, more than describedization of about 97 weight % Compound/salt/isomers, and the compound/salt/isomers more than about 99 weight %.
Composition
The disclosure also relates in part to the compound comprising one or more disclosure and/or the composition of its salt.At some In embodiment, composition includes one or more substantially mutually pure crystal form (substantially phase pure crystalline form).Composition can be pharmaceutical composition.
In some embodiments, composition further includes one or more other therapeutic agent.Such therapeutic agent can With the therapeutic agent for being used to treat Respiratory Syncytial Virus(RSV) including such as one or more（Such as current treatment standard）.
The component of composition can depend on medication, and can be comprising acceptable in one or more conventional pharmaceutical Carrier, adjuvant, and/or medium（Together it is referred to as " excipient "）.Pharmaceutical preparation is generally discussed at such as Hoover, J.,Remington's Pharmaceutical Sciences(Mack Publishing Co., 1975) and Ansel'sPharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott Williams & Wilkins, 2005)。
The pharmaceutical composition of the disclosure can, parenteral, sublingual, per rectum such as oral through number of ways, local or logical Inhalation is crossed in its patient of needs.Local administration can be directed to use with cutaneous penetration such as transdermal patch or electro-ionic osmosis and set It is standby.Parenteral is including but not limited to subcutaneous, intravenous, intramuscular or breastbone inner injection and infusion techniques.
Solid dosage forms for being administered orally includes such as capsule, tablet, pill, pulvis and granule.In such solid In formulation, the compound or salt of the disclosure generally with one or more excipient composition.If oral administration, compound or salt can With with such as lactose, sucrose, starch powder, the cellulose esters of alkanoic acid, cellulose alkyl esters, talcum, stearic acid, stearic acid The sodium salt and calcium salt of magnesium, magnesia, phosphoric acid and sulfuric acid, gelatin, Arabic gum, mosanom, polyvinylpyrrolidone and/poly- second Enol mixes, and is subsequently formed into tablet or capsule to facilitate administration.Such capsule or tablet can the systems containing controlled release Agent, dispersion that such as can be for example with compound or salt in hydroxypropyl methyl cellulose is provided.In capsule, tablet and ball In the case of agent, formulation can also include buffer, such as sodium citrate or magnesium carbonate or magnesium bicarbonate or calcium carbonate or carbonic acid Hydrogen calcium.Tablet and pill can prepare enteric coating in addition.
Liquid formulation for oral administration includes for example pharmaceutically acceptable emulsion（Including oil-in-water and water in oil emulsion Liquid）, solution（Including aqueous and not aqueous solution）, suspension（Including aqueous and not aqueous suspension）, syrup and contain this Usually used inert diluent in field（Such as water）Elixir.Such composition can also be comprising such as wetting agent, emulsification Agent, suspending agent, flavor enhancement（Such as sweetener）And/or aromatic.
Parenteral includes hypodermic injection, intravenous injection, intramuscular injection, breastbone inner injection and infusion.Injectable system Agent（Such as sterile injectable is aqueous or oleaginous suspension）Can according to known technology using suitable dispersant, wetting agent and/ Or suspending agent is prepared.Acceptable medium and solvent include such as water, 1,3 butylene glycol, Ringer's mixture, isotonic chlorination Sodium solution, gentle fixed oil（For example, the monoglyceride or diglyceride of synthesis）, aliphatic acid（Such as oleic acid）, dimethyl Acetamide, surfactant（For example, ionic and non-ionic detergent）, and/or polyethylene glycol.
The preparation of parenteral can for example from one or more tax with the formulations for oral administration for referring to It is prepared by the aseptic powdery or particle of shape agent.Compound of the invention or salt can be dissolved in water, polyethylene glycol, propane diols, second In alcohol, corn oil, cottonseed oil, peanut oil, sesame oil, phenmethylol, sodium chloride and/or various buffer solutions.If desired, conjunction can be used Suitable acid, alkali or buffer solution regulation pH.
Suppository for rectally can for example by by compound of the invention or salt and suitable nonirritant tax Shape agent mixes to prepare, and the nonirritant excipient is at normal temperatures solid, but is liquid under rectal temperature, and thus will Melt to discharge medicine in the rectum.Suitable excipient includes such as cocoa butter, monoglyceride, the diglyceride or sweet of synthesis Oily three esters, aliphatic acid, and/or polyethylene glycol.
Local administration is included using cutaneous penetration such as transdermal patch or electro-ionic osmosis equipment.
The compound or pharmaceutical composition of the disclosure can be formulated as being suitable for suction.Pharmaceutical composition can for solution, Suspension, powder or other be used for transpulmonary administration suitable form form.These compositions can suitably be passed by any Delivery method is such as through the equipment for implementing such delivering as known in the art with aerosol, atomization, spraying or vaporization Form deliver medicine to lung.The amount of disclosed pharmaceutical composition can be by such as in metered dose inhaler（metered dose inhalers, MDI）（It is with the activity each time of the device with spray delivery fixed dosage）It is middle to provide valve to deliver through metering Amount control.Pharmaceutical composition can be formulated with one or more suitable propellant such as dicholorodifluoromethane, three Chlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide or other suitable gases.For inhalator or the capsule and cartridge case of insufflator Can be formulated as the powder of compound or pharmaceutical composition containing the disclosure and suitable powder binder such as lactose or starch Mixture.
Pharmaceutical composition can be formulated with one or more adhesive as dried powder for sucking.
The compound or pharmaceutical composition of the disclosure can be the preparation of sustained release or controlled delivery.Prepare such sustained release and receive What the technology of control delivering preparation was well known to those skilled in the art.Wherein have and use liposome vectors, Bio-erodable (bio-erodible) delivering method of particulate, porous bead and semi-permeable polymer matrices.
Known other excipient and mode of administration can also be used in pharmaceutical field.
Total daily dosage of the compound or its salt of the disclosure（It is administered with single or broken dose）Can be about 0.001 to About 100 mg/kg, about 0.001 to about 30 mg/kg, or about 0.01 to about 10 mg/kg（That is, the compound of mg or salt/kg bodies Weight）.Dosage unit compositions can be measured containing as or its approximate number is to constitute daily dosage.In many cases, the disclosure The administration of compound or its salt will repeatedly.If desired, multidose is generally used for increasing total daily dosage daily.
Influenceing the factor of dosage regimen includes type, age, body weight, sex, diet and the patient's condition of patient；Pathological condition The order of severity；Method of administration；Pharmacology considers, particular compound such as used or the activity of salt, effect, pharmacokinetics and Toxicity characteristic；Whether drug delivery system is used；Period that wherein rsv infection is most likely to occur such as to determine that the RSV phases；And change Whether compound or salt are administered as a part for drug regimen.Therefore, the dosage regimen for actually using can change very big, and And therefore can be derived from dosage regimen mentioned above.
Kit
The disclosure also relates in part to the compound comprising one or more disclosure and/or the kit of its salt.Kit Can optionally containing one or more other therapeutic agent and/or for operating the specification such as using the kit.
Application method
Disclosure part is related to the method for the infection and/or the duplication that suppress RNA virus.Methods described includes exposing virus In one or more compound and/or its salt of the disclosure.In embodiments, RNA virus infection and/or replicate in vitro It is suppressed.In embodiments, the infection of RNA virus and/or duplication is suppressed in vivo.In embodiments, infection and/or It is RNA virus that are single-stranded, bearing justice to replicate repressed RNA virus.In embodiments, infect and/or replicate repressed RNA Virus is the virus from family of paramyxovirus section.In embodiments, infect and/or replicate repressed RNA virus and be RSV。
Term " suppression " represents the level for reducing that external or In vivo infection and/or RNA virus are replicated.Suppression can be acted on Virus infection and/or any stage replicated, such as（But not exclusively）Attachment, infiltration, shelling, genome duplication, assembling, into Cell discharge ripe or from infection.The target of compound can be the virus or host component for participating in virus infection and/or duplication （Or rarely for both）.If for example, picornavirus infection compared to virus before disclosed compound/salt and/ Or the level for replicating, the compound/salt reduces the level at least about 10% that infection and/or RNA virus are replicated, then describedization Compound/salt inhibits picornavirus infection and/or duplication.In some embodiments, compound/salt can suppress RNA virus sense Dye and/or replicate at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, At least about 80%, at least about 90% or at least about 95%.
The disclosure also relates in part to the method for treating the individual rsv infection for needing such treatment.These method bags Include the compound and/or salt to described individual one or more disclosure of administration and optionally one or more other treatment Agent.In some embodiments, to the compound and/or its salt of the individual drug treatment effective dose." treatment " is represented to be improved, Suppress, eradicate, preventing infection or disease to be treated, reducing its risk, and/or postpone its breaking-out.For example, the chemical combination of the disclosure Thing and/or its salt can be used for prevention to prevent the individual infection being uninfected by, and/or prevent virus infected with the virus Patient in lower respiratory tract propagation.Term " treatment " is included to the patient's administration disclosure in rsv infection risk Compound and/or its salt.Patient in rsv infection risk can be including premature, with bronchopulmonary dysplasia The people of children, the children with the congenital heart and lung disease, the elderly and compromised immune and because they are jejune or Worse immune system and other patients of enough immune responses cannot be produced.The compound of the disclosure and/or its salt can be with Deliver medicine to the patient low to the side effect tolerance of current therapy.
Treatment method is especially suitable for people, but it is also possible to for other animals." therapeutically effective amount " or " effective dose " is The amount of the target of the treatment targeting patient's condition can be substantially carried out.
In embodiments, disclosed method includes combination treatment, the wherein compound and/or salt and second of the disclosure Kind of compound, such as treating another therapeutic agent of RSV, such as current treatment standard, and other are disease-resistant Toxic agent co-administered.In the embodiment of these co-administereds, the compound and/or salt of the disclosure and second grade therapeutic agent Can be in a substantially simultaneous manner（For example, at least about 5 minutes each other）, in a sequential manner, or both be administered.Example Such as, the compound and/or salt of the disclosure can before with current treatment standard care, among or deliver medicine to patient afterwards, If it is considered to such administration is medically necessary and/or properly.
The disclosure also relates in part to have one using the compound and/or salt and optionally combination of one or more disclosure Kind or various other therapeutic agents prepare medicine.In some embodiments, medicine is used for other with one or more controlling Treat agent co-administered.
In some embodiments, the medicine is used to suppress the duplication of RNA virus.
In some embodiments, the medicine is used to treat RSV.
In embodiments, the compound and/or salt of one or more disclosure can be used for preventing and/or treat by group The rsv infection that one or two group of A or group B RSV viruses causes.
In embodiments, the compound and/or salt of one or more disclosure can be used for suppressing group A or group B RSV The infection and/or duplication of one or two group of virus.
The disclosure also relates in part to the compound and/or salt of one or more disclosure of the invention and optionally combination to be had One or more other therapeutic agent, for suppressing the duplication of RNA virus or for treating rsv infection.
Biological characteristis
Cell and virus
HEp-2 cells and RSV (group A, long-chain) are available from American Type Culture Collection (Manassas, VA)。
It is antiviral（RSV）Determine
Carry out cytopathic effect（CPE）Protection determine determine compound protection cell from virus infection and therefore by The ability of the infection induced CPE of virus.By 96 orifice plates first in the Dulbecco improvement containing 10% hyclone (FBS) With 3 × 10 in Eagle culture mediums (DMEM)3HEp-2 cells/wells are inoculated with.Inoculating cell one day after, by they with 100 μ L determines culture medium (with 1：1 ratio is mixed with the DMEM of F12 culture mediums, is added with 2% FBS and 1 mM Sodium Pyruvates) middle preparation The serial dilution of compound preincubate 1 hour at 37 DEG C.Then by 100 of the RSV containing 0.2 infection multiplicity (MOI) μ L determine culture medium and are added in every hole cell.In addition to the hole containing the cell with compound incubation through infecting, each Plate is also comprising two kinds of repetitions of control：（1）Virus control contains the thin of the RSV infected with 0.2 MOI in culture medium is determined Born of the same parents,（2）The cell controls being uninfected by contain only with the cell for determining culture medium incubation.After being incubated 4 days at 37 DEG C, MTT is used (tetrazolium bromide, Sigma) assesses cell viability.By MTT in phosphate buffered saline (PBS) concentration be 4 mg/mL stock solution with 25 μ L/ holes are added in all holes.Plate is further incubated for 4 hours, and each hole then contained 20% with 50 μ L Lauryl sodium sulfate (SDS) and 0.02NThe solution treatment of HCl.After night incubation, by plate in BioTek®Microtiter plate With the wavelength measurement of 570 nm and 650 nm on reader.MTT detections are based on work（It is uninfected by）Cell can be by tetrazolium salts also It is former into coloured first a ceremonial jade-ladle, used in libation（formazan）Product, it then can be quantified by AAS.Dividing based on each sample Optical absorbance, can calculate the percentage for protecting against CPE to every kind of compound（It is the index for protecting against virus infection）, And 50% valid density (EC50) nonlinear regression curve provided by the softwares of GraphPad Prism 4 can be used to be fitted Equation is calculated.Using said determination, compound of the invention shows the obvious inhibitory activity replicated for RSV.Result shows Show in table 1.
Cytotoxicity（MTT）Determine
The cytotoxicity of compound is determined in the experiment for carrying out parallel with antiviral measure.Therefore, 100 μ L are determined Culture medium is added in the hole of the HEp-2 cells pre-processed with the compound of 100 μ L serial dilutions as described above.It is incubated 4 days Afterwards, the vigor that cell is determined with the same procedure described in detail such as in " antiviral measure " method is determined by MTT.Result is expressed as 50% toxicity dose (TD50) value.Result is displayed in table 2.
Compound Test Strategy
Test compound is come the treatment window that determines their antiviral property and toxicity to determine them.These active ingredients The EC of thing50And TD50Measure be repeated once to determine window in addition.Result is displayed in table 2.
General synthesis
Compound on formula I（And its salt）Other information be provided in General Discussion hereafter and/or specific close Into in embodiment.In the following discussion, R1, R2, R3, R4, R5, R6, Rg, and G1With implication as described above, unless It is otherwise noted.
The compound of the disclosure can include methods described below and its variant to make by methods known in the art It is standby.
Some disclosed compounds can be prepared as being generally shown in scheme 1.Formula（1-1）Dichloro pyrimidine can be molten With amine R in agent such as ethanol1-NH(R6) react at ambient temperature or under heating, such as Martyn DC, etc.Bioorganic and Medicinal Chemistry Letters2010；20:Described in 228-231, carry out the compound of production (1-2).Formula（1-1） Dichloro pyrimidine can also be with amine R1-NH(R6) in solvent such asN,NIn alkali such as cesium carbonate or three second in-dimethylformamide Reacted with the compound of production (1-2) at ambient temperature or under heating in the presence of amine.The compound of formula (1-2) can With the feelings that the amine with formula (1-3) optionally exists in solvent such as acetonitrile, dioxs or isopropanol in acid such as hydrochloric acid/dioxs Under condition conventional heating or by microwave heating response come the compound of production (1-4).The compounds represented formula of formula (1-4) (I) compound.
Some disclosed compounds can be prepared as being generally shown in scheme 2.Formula（2-1）Compound can be with formula （1-3）Amine in solvent such as dimethyl sulfoxide conventional heating reaction or by microwave heating response come production (2-2) Compound.The compound of formula (2-2) can be with POCl3 (V) in catalytic amountN,N- dimethylformamide (DMF) is present In the case of heating response carry out the compound of production (2-3).The compound of formula (2-3) can be with amine R1-NH(R6) all in solvent As optionally heating response carrys out the chemical combination of production (1-4) in the presence of acid catalyst such as hydrochloric acid/dioxs in acetonitrile Thing.The compound of the compounds represented formula (I) of formula (1-4).
In foregoing scheme, it is shown that wherein aromatic ring（Such as phenyl）With specific region selectivity (regiochemistry)（For example, contraposition）Substitution has the compound of group.Initial substance or intermediate with contraposition substitution The end-product with contraposition substitution is provided in aforementioned schemes.It will be understood by those skilled in the art that with different zones selection Property（Such as meta）Initial substance or intermediate aforementioned schemes in substitution by provide with different zones selectivity end Product.For example, with meta replace initial substance or intermediate substitute aforementioned schemes in contraposition substitution initial substance or in Mesosome will form the product of meta substitution.
If group (for example ,-NH described herein2Or-OH) incompatible with synthetic method, then can be with to the side The suitable blocking group of the stable reaction conditions used in method protects the group.Blocking group can appoint in reaction sequence What suitable point removes to provide desired intermediate or target compound.Suitable guarantor for protecting or deprotecting group Shield group and method are well known in the art, and the example is found in Greene TW and Wuts PGM, Protective Groups in Organic Synthesis, (the 3rd edition, John Wiley ＆ Sons, NY (1999)).For each list Unrivalled rapid optimum reaction condition and reaction time can take according to present in specific reactant and reactant used used It is different for base.Solvent, temperature and other reaction conditions can easily be selected by those of ordinary skill in the art according to the disclosure Select.
It will be understood by those skilled in the art that other disclosed compounds can be according to such scheme and following centre Program described in the disclosure of body, program and embodiment is similarly prepared.It should be understood that the embodiment above and scheme and Following intermediate, general procedure and embodiment are disclosed and given by illustrative and not restrictive mode.In the range of the disclosure Variations and modifications will be apparent from this specification to those skilled in the art.
Embodiment
Abbreviation：DMSO is dimethyl sulfoxide；It is electron spray ionisation with ESI.
Embodiment 1
N 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Step A
Thio -2,3- the dihydro-pyrimidins -4 (1 of 5,6- dimethyl -2-H) -one
To adding 2- in agitating solution of the potassium tert-butoxide (15.71 g, 0.140 mol) in tetrahydrofuran (200 mL) Methyl-ethyl 3-oxobutanoate (20.0 g, 0.14 mol) and thiocarbamide (10.55 g, 0.14 mol) are in absolute ethyl alcohol Solution in (150 mL).The mixture of gained is flowed back 15 minutes and room temperature is cooled to.The precipitation to be formed is collected by filtration, Washed with tetrahydrofuran (200 mL), and be dissolved in water (200 mL).To addition acetic acid (100 mL) in the solution of gained. The precipitation to be formed is collected by filtration and dries to produce the title compound of 17g (78.5%).
Step B
5,6- dimethyl pyrimidines -2,4 (1H,3H)-diketone
By the thio -2,3- dihydro-pyrimidins -4 (1 of 5,6- dimethyl -2-H) -one (14.4 g, 0.09 mol, step A) and Solution at reflux overnight of the monoxone (100.0 g, 1.06 mol) in water (43mL), is cooled to room temperature and with water (500 mL) It is quenched.The precipitation to be formed is collected by filtration and dries to produce the title compound of 10.3 g (79.7 %).
Step C
The chloro- 5,6- dimethyl pyrimidines of 2,4- bis-
To 5,6- dimethyl pyrimidines -2,4 (1H,3H)-diketone (10.3 g, 0.07 mol, step B) is in POCl3 (V) dimethylformamide (0.2 ml) is added in the agitating solution in (150 mL).The mixture of gained is flowed back under argon gas Overnight and it is cooled to room temperature.The mixture of gained is evaporated.To addition toluene (200 mL) in residue.By the mixture of gained Concentration.To cold water (400 mL) of the addition containing ice in residue, and mixture is extracted into (3 × 150 mL) with chloroform.To close And organic layer salt water washing, it is dried over magnesium sulfate, filter simultaneously concentrate under reduced pressure.Crude product is existed by column chromatography Purified on silica gel, with ethyl acetate/hexane mixture (1:2-1:1) elute to produce the title compound of 9.5 g (73%).
Step D
2- is chloro-N- cyclohexyl -5,6- dimethyl pyrimidine -4- amine
To the chloro- 5,6- dimethyl pyrimidines of 2,4- bis- (9.3 g, 0.05 mol, step C) in dimethylformamide (100 ML cesium carbonate (37.6 g, 0.12 mol) is added in the agitating solution in).It is subsequently added cyclohexylamine (5.7 g, 0.058 Mol), the temperature of reactant mixture is kept at 70 DEG C.After 48 hours, reactant mixture is concentrated, and by residue with water (200 ML) it is quenched.The mixture of gained is extracted with dichloromethane (3 × 120 mL).The organic layer salt water washing that will merge, It is dried over magnesium sulfate, filter and concentrate.By distilling removal solvent, and crude product is purified by column chromatography on silica gel, With ethyl acetate/methanol (10:1---10:2) elute to produce the title compound of 4.9 g (38.9%).
Step E
N 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamine hydrochlorides
It is chloro- to 2-N- cyclohexyl -5,6- dimethyl pyrimidine -4- amine (0.1g, 0.40 mmol) and (pyridine -2- Ji Jia Base) 3.5 M in hydrochloric acid dioxs are added in agitating solution of the amine (0.04 g, 0.400 mmol) in acetonitrile (5 mL) Solution (0.2 mL).By the mixture of gained in CEM Focused Microwave Synthesis System 160 Irradiated 120 minutes at DEG C.The mixture of gained is cooled to room temperature.The precipitation to be formed is collected by filtration and dries to produce 0.07g (48.2%) is the title compound of hydrochloride.
Embodiment 2-4 can be prepared in the method described in operational version 1 and references cited therein.
Embodiment 2
N 4- (2- methyl-benzyls)-N 2- (pyridine -2- ylmethyls) -6,7- dihydros -5H- cyclopenta [d] pyrimidine -2,4- Diamines
。
Embodiment 3
N 4- suberyl -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
。
Embodiment 4
N 4- cyclohexyl -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
。
Embodiment 5
N 2- benzyl-N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) is produced slightly using benzylamine instead of (pyridine -2- ylmethyls) amine Product.By distilling removal solvent, and by HPLC purification of crude product (posts：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient:20-50% acetonitriles in 0.02% trifluoroacetic acid/water are 15 minutes；0.02% trifluoroacetic acid/ 50-100% acetonitriles in water are 5 minutes；Flow velocity：25 mL/min；Temperature：25℃).Obtain the title compound for white solid The trifluoroacetate of thing.
Embodiment 6
N 4- cyclohexyl -5,6- dimethyl -N 2- (pyridin-3-yl methyl) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) replaces (pyridine -2- Ji Jia using 1- pyridin-3-yls methylamine Base) amine to be producing crude product.By distilling removal solvent, and by HPLC purification of crude product (posts：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient:20-50% acetonitriles in 0.02% trifluoroacetic acid/water are 15 minutes； 50-100% acetonitriles in 0.02% trifluoroacetic acid/water are 5 minutes；Flow velocity：25 mL/min；Temperature：25 DEG C) producing title The trifluoroacetate of compound, is white solid.
Embodiment 7
2- ({ [4- (Cyclohexylamino) -5,6- dimethyl pyrimidine -2- bases] amino } methyl) -6- picoline -3- alcohol
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) is replaced using 2- (amino methyl) -6- picoline -3- alcohol (pyridine -2- ylmethyls) amine.Crude product purifies (post by HPLC：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient：20-50% acetonitriles in 0.02% trifluoroacetic acid/water are 15 minutes；In 0.02% trifluoroacetic acid/water In 50-100% acetonitriles be 5 minutes；Flow velocity：25 mL/min；Temperature：25 DEG C) producing the trifluoroacetic acid of title compound Salt, is white solid.
Embodiment 8
N 4- cyclohexyl-N 2- (4- methoxy-benzyls) -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (4- methoxy-benzyls) amine to replace (pyridine -2- Ji Jia Base) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and And then end-product is washed to produce title compound with ether, is white solid.
Embodiment 9
N 4- cyclohexyl-N 2- (4- luorobenzyls) -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (4- luorobenzyls) amine to replace (pyridine -2- ylmethyls) Amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and with End-product is washed to produce title compound with ether afterwards, is white solid.
Embodiment 10
N 4- cyclohexyl -5,6- dimethyl -N 2- [4- (trifluoromethoxy) benzyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1), the replacement of use [4- (trifluoromethoxy) benzyl] amine (pyridine - 2- ylmethyls) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out comes pure Change, and then end-product is washed to produce title compound with ether, is white solid.
Embodiment 11
N 4- cyclohexyl-N 2- (4- isopropyl benzyls) -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (4- isopropyl benzyls) amine to replace (pyridine -2- Ji Jia Base) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and And then end-product is washed to produce title compound with ether, is white solid.
Embodiment 12
N 4- cyclohexyl -5,6- dimethyl -N 2- [4- (trifluoromethyl) benzyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [4- (trifluoromethyl) benzyl] amine to replace (pyridine -2- Ylmethyl) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out comes pure Change, and then end-product is washed to produce title compound with ether, is white solid.
Embodiment 13
N 4- cyclohexyl-N 2- (3- luorobenzyls) -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (3- luorobenzyls) amine to replace (pyridine -2- ylmethyls) Amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and with End-product is washed to produce title compound with ether afterwards, is white solid.
Embodiment 14
N 4- cyclohexyl -5,6- dimethyl -N 2-(1H- pyrazoles -5- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (1H- pyrazoles -5- ylmethyls) amine replacement (pyridine -2- Ylmethyl) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out comes pure Change, and then end-product is washed to produce title compound with ether, is light yellow solid.
Embodiment 15
N 4- cyclohexyl -5,6- dimethyl -N 2-[(1R) -1- phenylethyls] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(1R) -1- phenylethyls] amine replacement (pyridine -2- bases Methyl) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, And subsequent end-product is washed to produce title compound with ether, is light yellow solid.
Embodiment 16
N 4- cyclohexyl -5,6- dimethyl -N 2-[(1S) -1- phenylethyls] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(1S) -1- phenylethyls] amine replacement (pyridine -2- bases Methyl) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, And subsequent end-product is washed to produce title compound with ether, is light yellow solid.
Embodiment 17
N 4- cyclohexyl -5,6- dimethyl -N 2- [(4- picoline -2- bases) methyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (4- picoline -2- bases) methylamine to replace (pyridine -2- Ylmethyl) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out comes pure Change, and then end-product is washed to produce title compound with ether, is light gray solid.
Embodiment 18
N 4- cyclohexyl-N 2- [(4-methoxypyridine -2- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(4-methoxypyridine -2- bases) methyl] amine to replace (pyridine -2- ylmethyls) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is washed Take off to purify, and then end-product is washed to produce title compound with ether, is light gray solid.
Embodiment 19
N 4- cyclohexyl -5,6- dimethyl -N 2- [(6- picoline -2- bases) methyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(6- picoline -2- bases) methyl] amine to replace (pyrrole Pyridine -2- ylmethyls) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out To purify, and then end-product is washed to produce title compound with ether, is light gray solid.
Embodiment 20
N 4- cyclohexyl -5,6- dimethyl -N 2- { [5- (trifluoromethyl) pyridine -2- bases] methyl } pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses { [5- (trifluoromethyl) pyridine -2- bases] methyl } amine generation For (pyridine -2- ylmethyls) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture Elute to purify, and then end-product is washed to produce title compound with ether, is light gray solid.
Embodiment 21
N 2- [(4- tert .-butylpyridine -2- bases) methyl] -N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(4- tert .-butylpyridine -2- bases) methyl] amine to replace (pyridine -2- ylmethyls) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is washed Take off to purify, and then end-product is washed to produce title compound with ether, is light gray solid.
Embodiment 22
N 4- cyclohexyl -5,6- dimethyl -N 2- (2- thienyl methyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (2- thienyl methyls) amine to replace (pyridine -2- Ji Jia Base) amine.Crude product is by from ethanol（10 mL）Middle crystallization purifying, to produce the hydrochloride of title compound, is light gray solid.
Embodiment 23
N 4- cyclohexyl-N 2- [(3,5- dimethyl -1,2- oxazole -4- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(3,5- dimethyl isoxazole -4- bases) methyl] amine generation For (pyridine -2- ylmethyls) amine.Product purifies (post by HPLC：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient：20-50% acetonitriles in 0.02% trifluoroacetic acid/water are 15 minutes；In 0.02% trifluoroacetic acid/water In 50-100% acetonitriles be 5 minutes；Flow velocity：25 mL/min：Temperature：25 DEG C) producing the trifluoroacetic acid of title compound Salt, is white solid.
Embodiment 24
N 4- cyclohexyl -5,6- dimethyl -N 2- [(1- methyl isophthalic acidsH- imidazol-4 yl) methyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(1- methyl isophthalic acidsH- imidazol-4 yl) methyl] amine replacement (pyridine -2- ylmethyls) amine.Product is by from ethanol（10 mL）Middle crystallization purifying is to produce the hydrochloride of title compound White solid.
Embodiment 25
N 4- cyclohexyl-N 2- (3- methoxy-benzyls) -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses (3- methoxy-benzyls) amine to replace (pyridine -2- Ji Jia Base) amine.Crude product is by from ethanol（10 mL）Middle crystallization purifying, to produce the hydrochloride of title compound, is white solid.
Embodiment 26
N 4- cyclohexyl -5,6- dimethyl -N 2- [(3- picoline -2- bases) methyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(3- picoline -2- bases) methyl] amine to replace (pyrrole Pyridine -2- ylmethyls) amine.Crude product is by from ethanol（10 mL）Middle crystallization purifying, to produce the hydrochloride of title compound, is white Color solid.
Embodiment 27
N 2- [(4- chloropyridine -2- bases) methyl] -N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1), the replacement of use [(4- chloropyridine -2- bases) methyl] amine (pyridine - 2- ylmethyls) amine.Crude product is by from ethanol（10 mL）Middle crystallization purifying, to produce the hydrochloride of title compound, is white Solid.
Embodiment 28
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- [(4- picoline -2- bases) methyl] pyrimidine -2,4- diamines
Step A
2- is chloro-N- (4,4- difiuorocyclohexyls) -5,6- dimethyl pyrimidine -4- amine
Exist to the chloro- 5,6- dimethyl pyrimidines of 2,4- bis- (0.585g, 3.304 mmol, embodiment 1, step C)N,N- (4,4- difiuorocyclohexyls) amine hydrochlorate (0.652 g, 3.800 are added in solution in dimethylformamide (10 mL) Mmol) and triethylamine (1.338 g, 13.218 mmol), and reactant mixture is heated overnight at 50 DEG C.Under reduced pressure Removal volatile matter, and residue is poured into water（300 mL）In.Mixture is extracted with ether (3 × 50 mL), through sodium sulphate It is dried, filtered and concentrated.Residue is carried out into column chromatography on silica, with the mixture (ladder of hexane/ethyl acetate Degree 4:1 - 2:1) elute to produce the title compound of 621 mg (68%), be white solid.
Step B
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- [(4- picoline -2- bases) methyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(4- picoline -2- bases) methyl] amine to replace (pyrrole Pyridine -2- ylmethyls) amine and 2- it is chloro-N- (4,4- difiuorocyclohexyls) -5,6- dimethyl pyrimidines -4- amine (step A) replaces 2- chloro-N- cyclohexyl -5,6- dimethyl pyrimidine -4- amine.By the crystallization purifying from ethanol, to produce title compound, (45% produces product Rate) hydrochloride, be light yellow solid.
Embodiment 29
N 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Step A
5,6- dimethyl -2- (methyl mercapto) pyrimidine -4 (3H) -one
At room temperature to the thio -2,3- dihydro-pyrimidins -4 (1 of 5,6- dimethyl -2-H) -one (10.0 g, 64.0 mmol, Embodiment 1, step A) and agitating solution of the NaOH (10.0 g, 260.0 mmol) in water (150 mL) in add Iodomethane (15.0 g, 320.0 mmol), and reactant mixture is stirred at room temperature overnight.Then reactant mixture is used Acetic acid（50 mL）Acidifying, and solid by filtration is collected and dries to produce the title compound of 7.0 g (64%), it is white Color solid.
Step B
5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine -4 (3H) -one
Stirring to (pyridine -2- ylmethyls) amine (5.8g, 54 mmol) in dimethyl sulfoxide (15 mL) at room temperature 5,6- dimethyl -2- (methyl mercapto) pyrimidine -4 (3 is added in solutionH) -one (7 g, 41 mmol, step A), and gained is mixed Compound is stirred overnight at 150 DEG C.Then by water（100 mL）It is carefully added into thermal reaction mixture.After being cooled to room temperature, plus Enter ether (30 mL).The precipitation to be formed is collected by filtration, and dries to produce the title compound of 7.0 g (74%), be White solid.
Step C
The chloro- 5,6- dimethyl of 4--N- (pyridine -2- ylmethyls) pyrimidine -2- amine
By added with 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine -4 (3 of 1 drop dimethylformamideH)- Solution of the ketone (7.0 g, 32.6 mmol, step B) in POCl3 (V) (30 mL) flows back overnight under a nitrogen.So Excessive POCl3 (V) is removed under reduced pressure afterwards.Add toluene（30 mL）, then reactant mixture is steamed under reduced pressure Hair.Residue is diluted with 5% sodium bicarbonate aqueous solution (100 mL) and is extracted with ethyl acetate (mL of 2 x 200).Will be molten Agent is evaporated under reduced pressure, and residue is carried out into column chromatography hexane/ethyl acetate (2:1) elute.Obtain title compound 6.1 g (74%), are light yellow solid.
Step D
N 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
By the chloro- 5,6- dimethyl of 4--N- (pyridine -2- ylmethyls) pyrimidine -2- amine (200 mg, 0.8 mmol, step ) and hydrochloric acid (0.2 mL) of the solution in 3.5 M dioxs of the cyclopentamine (85 mg, 1 mmol) in acetonitrile (5 mL) C Treatment, and by the backflow of gained mixture overnight.By reactant mixture water（50 mL）Dilution, and by gained precipitation by filtering Collect.Precipitation is by from ethanol（10 mL）Middle crystallization purifying is to produce the hydrochloride of the title compound of 42 mg (19%) White solid.
Embodiment 30
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (tetrahydrochysene -2H- pyrans -4- bases) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), use tetrahydrochysene -2H- pyrans -4- amine replaces cyclopentamine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be light yellow solid.
Embodiment 31
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethyl) cyclohexyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using 4- (trifluoromethyl) cyclohexylamine.Thick material (post is purified by HPLC：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient：0.02% 3 20-50% acetonitriles in fluoroacetic acid/water are 15 minutes；50-100% acetonitriles in 0.02% trifluoroacetic acid/water are 5 minutes；Stream Speed：25 mL/min：Temperature：25 DEG C) it is white solid to produce the trifluoroacetate of title compound.
Embodiment 32
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
By the chloro- 5,6- dimethyl-N -s of 4- (pyridine -2- ylmethyls) pyrimidine -2- amine, (200 mg, 0.8 mmol are implemented Example 29, step C) and solution of (4,4- difiuorocyclohexyls) amine hydrochlorate (172 mg, 1 mmol) in acetonitrile (5 mL) return Flow through night.By reactant mixture water（50 mL）Dilution, and the precipitation of formation is collected by filtration.Thick material passes through HPLC Purifying (post：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient：In 0.02% trifluoroacetic acid/water In 20-50% acetonitriles be 15 minutes；50-100% acetonitriles in 0.02% trifluoroacetic acid/water are 5 minutes；Flow velocity：25 mL/ min：Temperature：25 DEG C) to produce 114 mg, the trifluoroacetate of 25% title compound is white solid.
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines trifluoroacetic acids Salt passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify to produce 58 mg (68%) title compound, is white solid.
Embodiment 33
N 4- (2,3- dihydros -1H- indenes -1- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), use 2,3- dihydros -1H- indenes -1- base amine indane -1- amine replaces ring Amylamine.Thick material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and And then end-product is washed to produce title compound with ether, is white solid.
Embodiment 34
3- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclopentanol
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using 3- Aminocyclopentanol hydrochlorides.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 35
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (1,2,3,4- naphthane -1- bases) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), using 1,2,3,4- naphthane -1- base amine replace cyclopentamine.Thick thing Matter passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then eventually Product is washed to produce title compound with ether, is white solid.
Embodiment 36
N 4- (3,4- dihydros -2H- chromene -4- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), use 3,4- dihydros -2H- chromene -4- base amine replaces cyclopentamine.Slightly Material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then End-product is washed to produce title compound with ether, is white solid.
Embodiment 37
Cis -4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) -1- methyl cyclohexanes Alcohol
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), using cis-4- amino -1 methyl cyclohexanol replaces cyclopentamine. Thick material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and with End-product is washed to produce title compound with ether afterwards, is white solid.
Embodiment 38
It is trans-4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) -1- methyl cyclohexanes Alcohol
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), using trans-4- amino -1 methyl cyclohexanol replaces cyclopentamine. Thick material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and with End-product is washed to produce title compound with ether afterwards, is white solid.
Embodiment 39
N 4- (two rings [2.2.1] hept- 2- yls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using two rings [2.2.1] hept- 2- base amine.Thick thing Matter passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then eventually Product is washed to produce title compound with ether, is white solid.
Embodiment 40
5,6- dimethyl-N 4- (2- methylcyclohexyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using 2- methyl cyclohexylamines.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 41
N 4- (2,3- Dimethylcyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using 2,3- dimethyl cyclohexyl amines.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be white solid.
Embodiment 42
2- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using 2- aminocyclohexanols.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 43
Racemic-[(1R,2S) -2- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) Cyclohexyl] methyl alcohol
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), use racemic-[(1R,2S) -2- aminocyclohexyls] methyl alcohol generation For cyclopentamine.Thick material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out comes pure Change, and then end-product is washed to produce title compound with ether, is white solid.
Embodiment 44
N 4- (cyclopentyl-methyl) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (cyclopentyl-methyl) amine to replace cyclopentamine.Thick material passes through Column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is used Ether is washed to produce title compound, is white solid.
Embodiment 45
N 4- suberyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using 1- cycloheptylaminos.Thick material passes through post color Spectrometry chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product ether Washing, to produce title compound, is white solid.
Embodiment 46
N 4- (2,3- dihydros -1H- indenes -2- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), use 2,3- dihydros -1H- indenes -2- base amine replaces cyclopentamine.Thick thing Matter passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then eventually Product is washed to produce title compound with ether, is white solid.
Embodiment 47
N 4- cyclobutyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using ring butylamine.Thick material passes through column chromatography With chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is washed with ether It is white solid to produce title compound.
Embodiment 48
5,6- dimethyl-N 4- (pentane -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using ring butylamine.Thick material passes through column chromatography With chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is washed with ether It is white solid to produce title compound.
Embodiment 49
N 4- (3- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (3- fluorophenyls) amine hydrochlorate to replace cyclopentamine.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 50
N 4- (4- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (4- fluorophenyls) amine to replace cyclopentamine.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 51
N 4- (2- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (2- fluorophenyls) amine to replace cyclopentamine.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 52
5,6- dimethyl-N 4- phenyl-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using aniline.Thick material is used by column chromatography Chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out is purified, and then end-product washed with ether with Title compound is produced, is light gray solid.
Embodiment 53
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [3- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses [3- (trifluoromethoxy) phenyl] amine to replace cyclopentamine.Slightly Material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then End-product is washed to produce title compound with ether, is white solid.
Embodiment 54
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [3- (trifluoromethyl) phenyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses [3- (trifluoromethyl) phenyl] amine to replace cyclopentamine.Thick thing Matter passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then eventually Product is washed to produce title compound with ether, is white solid.
Embodiment 55
N 4- (2,6- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (2,6- difluorophenyl) amine to replace cyclopentamine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be white solid.
Embodiment 56
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses [4- (trifluoromethoxy) phenyl] amine to replace cyclopentamine.Slightly Material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then End-product is washed to produce title compound with ether, is light yellow solid.
Embodiment 57
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethyl) phenyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses [4- (trifluoromethyl) phenyl] amine to replace cyclopentamine.Thick thing Matter passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then eventually Product is washed to produce title compound with ether, is light yellow solid.
Embodiment 58
N 4- (3,4- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (3,4- difluorophenyl) amine to replace cyclopentamine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be light yellow solid.
Embodiment 59
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [2- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses [2- (trifluoromethoxy) phenyl] amine to replace cyclopentamine.Slightly Material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then End-product is washed to produce title compound with ether, is light yellow solid.
Embodiment 60
N 4- (2,5- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (2,5- difluorophenyl) amine to replace cyclopentamine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be light yellow solid.
Embodiment 61
N 4- (1,3- benzodioxole -5- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- Diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using 1,3- benzodioxole -5- amine. Thick material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and with End-product is washed to produce title compound with ether afterwards, is white solid.
Embodiment 62
N 4- (4- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (4- chlorphenyls) amine to replace cyclopentamine.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 63
5,6- dimethyl-N 4- (4- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using para-totuidine.Thick material passes through column chromatography Method chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is washed with ether Wash to produce title compound, be white solid.
Embodiment 64
N 4- (3,5- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (3,5- difluorophenyl) amine to replace cyclopentamine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be white solid.
Embodiment 65
N 4- (3- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (3- chlorphenyls) amine to replace cyclopentamine.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 66
N 4- (2- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (2- chlorphenyls) amine to replace cyclopentamine.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 67
5,6- dimethyl-N 4- (2- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using ortho-aminotoluene.Thick material passes through column chromatography Method chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is washed with ether Wash to produce title compound, be white solid.
Embodiment 68
N 4- (2,6- 3,5-dimethylphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (2,6- 3,5-dimethylphenyl) amine to replace cyclopentamine.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 69
5,6- dimethyl-N 4- (3- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using meta-aminotoluene.Thick material material passes through post color Spectrometry chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product ether Washing, to produce title compound, is white solid.
Embodiment 70
N 4- (1,1- titanium dioxide thiophane -3- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- two Amine
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (1,1- titanium dioxide tetrahydrochysene -3- thienyls) amine to replace ring penta Amine.Thick material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and Subsequent end-product is washed to produce title compound with ether, is white solid.
Embodiment 71
N 4- (5- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (5- fluoro-2-methylbenzenes base) amine to replace cyclopentamine.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 72
N 4- (the fluoro- 6- aminomethyl phenyls of 2-) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (the fluoro- 6- aminomethyl phenyls of 2-) amine to replace cyclopentamine.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 73
N 4- (the fluoro- 2- aminomethyl phenyls of 4,5- bis-) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (4,5- bis- fluoro- 2- aminomethyl phenyls) amine to replace cyclopentamine.Slightly Material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then End-product is washed to produce title compound with ether, is white solid.
Embodiment 74
5,6- dimethyl-N 4- (1- methyl isophthalic acidsH- pyrazoles -5- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), use 1- methyl isophthalic acidsH- pyrazoles -5- amine replaces cyclopentamine.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 75
N 4- (4- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (4- fluoro-2-methylbenzenes base) amine to replace cyclopentamine.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 76
N 4- (3- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (3- fluoro-2-methylbenzenes base) amine to replace cyclopentamine.Thick material By column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then produces eventually Thing is washed to produce title compound with ether, is white solid.
Embodiment 77
N 4- cyclohexyl-N 4, 5,6- trimethyls-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), useN- methyl cyclohexylamine replaces cyclopentamine.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 78
N 4- (3,3- Difluorocyclopentyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using 3,3- Difluorocyclopentyl amine hydrochlorates.Slightly Material passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then End-product is washed to produce title compound with ether, is white solid.
Embodiment 79
It is trans-4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), using trans-4- aminocyclohexanols replace cyclopentamine.Thick material is led to From ethanol crystallization purifying is crossed to produce the hydrochloride of title compound, is white solid.
Embodiment 80
N 4- (3,3- difiuorocyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (3,3- difiuorocyclohexyl) amine hydrochlorate to replace cyclopentamine. Thick material purifies (post by HPLC：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient： 20-50% acetonitriles in 0.02% trifluoroacetic acid/water are 15 minutes；50-100% acetonitriles in 0.02% trifluoroacetic acid/water are 5 minutes；Flow velocity：25 mL/min：Temperature：25 DEG C) it is white solid to produce the trifluoroacetate of title compound.
Embodiment 81
5,6- dimethyl-N 4- (1- methyl piperidine -4- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using 1- methyl piperidine -4- amine.Thick material passes through Column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is used Ether is washed to produce title compound, is light gray solid.
Embodiment 82
4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) tertiary fourth of piperidines -1- formic acid Ester
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using 1- methyl piperidine -4- amine.Thick material passes through Column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is used Ether is washed to produce title compound, is light gray solid.
Embodiment 83
5,6- dimethyl-N 4- (piperidin-4-yl)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
By 4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) piperidines -1- formic acid uncles Butyl ester (100 mg, 0.24 mmol, embodiment 82) is suspended in the 3 M solution (10 mL) in hydrochloric acid dioxs.Will be anti- Answer mixture to be stirred at room temperature overnight, and then remove solvent under reduced pressure.By residue by flash chromatography in silicon Chloroform/ethanol/20% ammonia spirit (200 is used on glue:10:1) mixture elutes to purify to produce title compound, is shallow Gray solid.
Embodiment 84
N 4- (2,6- diisopropyl phenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (2,6- diisopropyl phenyl) amine to replace cyclopentamine.Thick thing Matter passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then eventually Product is washed to produce title compound with ether, is white solid.
Embodiment 85
3- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using 3- aminocyclohexanols.Thick material by from Crystallization purifying, to produce the hydrochloride of title compound, is white solid in ethanol.
Embodiment 86
N 4- cyclohexyl -5,6- dimethyl -N 2- [(5- picoline -2- bases) methyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(5- picoline -2- bases) methyl] amine to replace (pyrrole Pyridine -2- ylmethyls) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture wash-out To purify, and then end-product is washed to produce title compound with ether, is white solid.
Embodiment 87
N 4- cyclohexyl -5,6- dimethyl -N 2- [1- (pyridine -2- bases) ethyl] pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 1) uses (1- pyridine -2- bases ethyl) amine to replace (pyridine -2- Ji Jia Base) amine.Product passes through column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and And then end-product is washed to produce title compound with ether, is white solid.
Embodiment 88
N 4- (2,4 difluorobenzene base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (2,4- difluorophenyl) amine to replace cyclopentamine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be white solid.
Embodiment 89
5- ethyls-N 4- (4- fluorophenyls) -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Step A
The chloro- 5- ethyls of 2--N- (4- fluorophenyls) -6- methylpyrimidine -4- amine
Title compound synthesizes as follows：According to chloro- for preparing 2-N- cyclohexyl -5,6- dimethyl pyrimidine -4- amine is (real Apply example 1, step D) described by program, replace chloro- 5, the 6- diformazans of 2,4- bis- using the chloro- 5- ethyls -6- methylpyrimidines of 2,4- bis- Yl pyrimidines and 4- fluoroanilines replace cyclo-hexylamine.Title compound is obtained, is white solid.。
Step B
5- ethyls-N 4- (4- fluorophenyls) -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1), using the chloro- 5- ethyls of 2- -N- (4- fluorophenyls) -6- methyl is phonetic Pyridine -4- amine (step A) replaces 2- chloro-N- cyclohexyl -5,6- dimethyl pyrimidine -4- amine.Product by column chromatography chloroform/ Ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is washed to produce mark with ether Topic compound, is light gray solid.
Embodiment 90
N 4- (4,4- difiuorocyclohexyls)-N 2- [(4- ethylpyridine -2- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines
Step A
2- is chloro-N- (4,4- difiuorocyclohexyls) -5,6- dimethyl pyrimidine -4- amine
Exist to the chloro- 5,6- dimethyl pyrimidines of 2,4- bis- (0.585 g, 3.304 mmol)N,N- dimethylformamide (10 ML (4,4- difiuorocyclohexyls) amine hydrochlorate (0.652 g, 3.800 mmol) and triethylamine are added in the solution in) (1.338 g, 13.218 mmol), and reactant mixture is heated overnight at 50 DEG C.Volatile matter is removed under reduced pressure, and will Residue pours into water（300 mL）In.Product is extracted with ether (3 × 50 mL), it is dried over sodium sulfate, filter and in decompression Lower concentration.Residue is carried out into column chromatography on silica, with the mixture (gradient 4 of hexane/ethyl acetate:1 - 2: 1) elute to produce the title compound of 621 mg (68%), be white solid.
Step B
N 4- (4,4- difiuorocyclohexyls)-N 2- [(4- ethylpyridine -2- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the general procedure described by 4- diamines (embodiment 1) uses [(4- ethylpyridine -2- bases) methyl] amine to replace (pyrrole Pyridine -2- ylmethyls) amine and 2- it is chloro-N- (4,4- difiuorocyclohexyls) -5,6- dimethyl pyrimidines -4- amine (step A) replaces 2- chloro-N- cyclohexyl -5,6- dimethyl pyrimidine -4- amine.Product is by the crystallization purifying from ethanol producing the hydrochloric acid of title compound Salt, is light yellow solid.
Embodiment 91
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (tetrahydrofuran -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (tetrahydrofuran -2- ylmethyls) amine to replace cyclopentamine.Thick thing Matter purifies (post by HPLC：YMC-PACK ODS-AQ C18, 250 mm × 20 mm, 10 µm；Gradient：0.02% 20-50% acetonitriles in trifluoroacetic acid/water are 15 minutes；50-100% acetonitriles in 0.02% trifluoroacetic acid/water are 5 minutes； Flow velocity：25 mL/min：Temperature：25 DEG C) it is light gray solid to produce the trifluoroacetate of title compound.
Embodiment 92
N 4- (cyclohexyl methyl) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), cyclopentamine is replaced using 1- cyclohexylmethylamines.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Embodiment 93
5,6- dimethyl-N 4- (pyridin-3-yl)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using pyridine -3- amine.Thick material passes through column chromatography Method chloroform/ethanol/20% ammonia spirit (200:10:1) mixture is eluted to purify, and then end-product is washed with ether Wash to produce title compound, be white solid.
Embodiment 94
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (1,3,4- thiadiazoles -2- bases) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29), using 1,3,4- thiadiazoles -2- amine replace cyclopentamine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be white solid.
Embodiment 95
5,6- dimethyl-N 4- (1,2- oxazole -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using isoxazole -3- amine.Thick material passes through post color Spectrometry chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product ether Washing, to produce title compound, is white solid.
Embodiment 96
5,6- dimethyl-N 4- (5- methyl isophthalic acids, 2- oxazole -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) replaces cyclopentamine using 5- methyl-isoxazole -3- amine.Thick material is led to Cross column chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product Washed to produce title compound with ether, be white solid.
Embodiment 97
N 4- (4- luorobenzyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines
Title compound synthesizes as follows：According to for preparingN 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) Pyrimidine -2, the program described by 4- diamines (embodiment 29) uses (4- luorobenzyls) amine to replace cyclopentamine.Thick material passes through post Chromatography chloroform/ethanol/20% ammonia spirit (200:10:1) mixture elutes to purify, and then end-product second Ether is washed to produce title compound, is white solid.
Above-cited all bibliography（Patent and non-patent）It is incorporated by reference into the patent application.Those are with reference to text The discussion offered is only intended to summarize its author's proposal.Any bibliography is not recognized completely（Or the portion of any bibliography Point）It is related art（Or prior art）.Applicant retains the accuracy and correlation of the bibliography for refuting cited Right.

Claims (9)

1. there is formula（I）Compound, or its pharmaceutically acceptable salt,
Wherein：
R1It is cyclohexyl, it is optionally replaced by 1,2,3 or 4 selected from following substitution base：C1-C10- alkyl, C2-C10- alkenyl, C2-C10- alkynyl, C1-C10- haloalkyl, C2-C10- haloalkenyl group, C2-C10- halo alkynyl, halogen, oxo, cyano group, hydroxyl ,- O-C1-C6- alkyl ,-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-O-H ,-C1-C3- alkylidene-O-C1-C6- alkyl ,-C1- C3- alkylidene-O-C1-C6- haloalkyl ,-C1-C3- alkylidene-NH2、-NH2、-C(O)O-C1-C6- alkyl ,-N (Rb1)C(O) Rb1、-CON(Ra1)(Rb1)、-C(O)Rb1、-OC(O)Rb1、-OS(O)2N(Ra1)(Rb1)、-CO2H、-CO2Rb1、-N(Rb1)C(O)N (Rb1)2、-S-Rb1、-S(O)2Rb1、-S(O)Rb1、-SO2N(Ra1)(Rb1)、-N(Ra1)(Rb1)、-N(Rb1)S(O)2Rb1、-N(Rb1)C (O)O(Rb1)、-N(Rb1)S(O)2O(Rb1)、-L1a-O-Rb1、-L1a-CN、-L1a-N(Rb1)C(O)Rb1、-L1a-CON(Ra1) (Rb1)、-L1a-C(O)Rb1、-L1a-OC(O)Rb1、-L1a-CO2H、-L1a-CO2Rb1、-L1a-N(Rb1)C(O)N(Rb1)2、-L1a-S- Rb1、-L1a-S(O)2Rb1、-L1a-S(O)Rb1、-L1a-SO2N(Ra1)(Rb1)、-L1a-N(Ra1)(Rb1)、-L1a-N(Rb1)S(O)2Rb1 And L1a-N(Rb1)C(O)O(Rb1)；
R2It is methyl or ethyl；
R3It is methyl or ethyl；
R4And R5Independently selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
R6Selected from hydrogen, C1-C6- alkyl and C1-C6- haloalkyl；
G1It is pyridine radicals, it is optionally replaced by 1,2,3,4 or 5 selected from following substitution base：Halogen, C1-C6- alkyl, C1- C6- haloalkyl ,-O-Rf、-CN、-N(Rf)C(O)Rf、-CON(Re)(Rf)、-C(O)Rf、-OC(O)Rf、-CO2H、-CO2Rf、-N (Rf)C(O)N(Rf)2、-S-Rf、-S(O)2Rf、-S(O)Rf、-SO2N(Re)(Rf)、-N(Re)(Rf)、-N(Rf)S(O)2Rf、-N (Rf)C(O)O(Rf)、-L3-O-Rf、-L3-CN、-L3-N(Rf)C(O)Rf、-L3-CON(Re)(Rf)、-L3-C(O)Rf、-L3-OC(O) Rf、-L3-CO2H、-L3-CO2Rf、-L3-N(Rf)C(O)N(Rf)2、-L3-S-Rf、-L3-S(O)2Rf、-L3-S(O)Rf、-L3-SO2N (Re)(Rf)、-L3-N(Re)(Rf)、-L3-N(Rf)S(O)2RfWith-L3-N(Rf)C(O)O(Rf)；
X is selected from O or NRg；
Ra1Hydrogen, C are each independently when occurring every time1-C6- alkyl, C1-C6- haloalkyl or C3-C8- cycloalkyl, wherein institute State C3-C8- cycloalkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：Halogen, oxo, C1-C3Alkyl and C1- C3- haloalkyl；
Rb1It is each independently hydrogen, C1-C6- alkyl or C1-C6- haloalkyl；
ReHydrogen, C are each independently when occurring every time1-C6- alkyl, C1-C6- haloalkyl or C3-C8- cycloalkyl, wherein institute State C3-C8- cycloalkyl is optionally replaced by 1,2,3 or 4 selected from following substitution base：Halogen, oxo, C1-C3Alkyl and C1- C3- haloalkyl；
RfIt is each independently hydrogen, C1-C6- alkyl or C1-C6- haloalkyl；
RgIt is hydrogen or C1- alkyl；
L1aC is each independently when occurring every time1-C6- alkylidene or C3-C8- cycloalkyl, wherein L1aEach optionally by 1,2,3 Or 4 halogens or 1 or 2 hydroxyl are replaced；And
L3C is each independently when occurring every time1-C6- alkylidene or C3-C8- cycloalkyl, wherein L3Each optionally by 1,2,3 Or 4 halogens are replaced.
2. the compound of claim 1, wherein X is O.
3. the compound of claim 1, wherein R2And R3Respectively methyl；R4、R5And R6 Respectively hydrogen；And X is NRg, wherein Rg It is hydrogen.
4. compound, it is selected from：
N 4- cyclohexyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 2- benzyl-N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- (pyridin-3-yl methyl) pyrimidine -2,4- diamines；
2- ({ [4- (Cyclohexylamino) -5,6- dimethyl pyrimidine -2- bases] amino } methyl) -6- picoline -3- alcohol；
N 4- cyclohexyl-N 2- (4- methoxy-benzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (4- luorobenzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [4- (trifluoromethoxy) benzyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (4- isopropyl benzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [4- (trifluoromethyl) benzyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (3- luorobenzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2-(1H- pyrazoles -5- ylmethyls) pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2-[(1R) -1- phenylethyls] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2-[(1S) -1- phenylethyls] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(4- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- [(4-methoxypyridine -2- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(6- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- { [5- (trifluoromethyl) pyridine -2- bases] methyl } pyrimidine -2,4- diamines；
N 2- [(4- tert .-butylpyridine -2- bases) methyl] -N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- (2- thienyl methyls) pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- [(3,5- dimethyl -1,2- oxazole -4- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(1- methyl isophthalic acidsH- imidazol-4 yl) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 2- (3- methoxy-benzyls) -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(3- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 2- [(4- chloropyridine -2- bases) methyl] -N 4- cyclohexyl -5,6- dimethyl pyrimidine -2,4- diamines；
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- [(4- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 4- cyclopenta -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (tetrahydrochysene -2H- pyrans -4- bases) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethyl) cyclohexyl] pyrimidine -2,4- diamines；
N 4- (4,4- difiuorocyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,3- dihydros -1H- indenes -1- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
3- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclopentanol；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (1,2,3,4- naphthane -1- bases) pyrimidine -2,4- diamines；
N 4- (3,4- dihydros -2H- chromene -4- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
Cis -4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) -1 methyl cyclohexanol；
It is trans-4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) -1 methyl cyclohexanol；
N 4- (two rings [2.2.1] hept- 2- yls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (2- methylcyclohexyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,3- Dimethylcyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
2- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol；
[(1R,2S) -2- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexyl] first Alcohol；
N 4- (cyclopentyl-methyl) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- suberyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,3- dihydros -1H- indenes -2- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- cyclobutyl -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (pentane -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (4- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2- fluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- phenyl-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [3- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [3- (trifluoromethyl) phenyl] pyrimidine -2,4- diamines；
N 4- (2,6- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [4- (trifluoromethyl) phenyl] pyrimidine -2,4- diamines；
N 4- (3,4- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- [2- (trifluoromethoxy) phenyl] pyrimidine -2,4- diamines；
N 4- (2,5- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (1,3- benzodioxole -5- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (4- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (4- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3,5- difluorophenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2- chlorphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (2- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,6- 3,5-dimethylphenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (3- aminomethyl phenyls)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (1,1- titanium dioxide thiophane -3- bases) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (5- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (the fluoro- 6- aminomethyl phenyls of 2-) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (the fluoro- 2- aminomethyl phenyls of 4,5- bis-) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (1- methyl isophthalic acidsH- pyrazoles -5- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (4- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3- fluoro-2-methylbenzenes base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- cyclohexyl-N 4, 5,6- trimethyls-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (3,3- Difluorocyclopentyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
Trans -4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol；
N 4- (3,3- difiuorocyclohexyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (1- methyl piperidine -4- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
4- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) piperidines -1- t-butyl formates；
5,6- dimethyl-N 4- (piperidin-4-yl)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (2,6- diisopropyl phenyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
3- ({ 5,6- dimethyl -2- [(pyridine -2- ylmethyls) amino] pyrimidine-4-yl } amino) cyclohexanol；
N 4- cyclohexyl -5,6- dimethyl -N 2- [(5- picoline -2- bases) methyl] pyrimidine -2,4- diamines；
N 4- cyclohexyl -5,6- dimethyl -N 2- [1- (pyridine -2- bases) ethyl] pyrimidine -2,4- diamines；
N 4- (2,4 difluorobenzene base) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5- ethyls-N 4- (4- fluorophenyls) -6- methyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (4,4- difiuorocyclohexyls)-N 2- [(4- ethylpyridine -2- bases) methyl] -5,6- dimethyl pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (tetrahydrofuran -2- ylmethyls) pyrimidine -2,4- diamines；
N 4- (cyclohexyl methyl) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (pyridin-3-yl)-N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 2- (pyridine -2- ylmethyls) -N 4- (1,3,4- thiadiazoles -2- bases) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (1,2- oxazole -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；
5,6- dimethyl-N 4- (5- methyl isophthalic acids, 2- oxazole -3- bases) -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines；With
N 4- (4- luorobenzyls) -5,6- dimethyl -N 2- (pyridine -2- ylmethyls) pyrimidine -2,4- diamines.
5. pharmaceutical composition, its compound for including any one of one or more claim 1-4 or its is pharmaceutically acceptable Salt；One or more excipient；With choose any one kind of them or various other therapeutic agents.
6. the compound or its pharmaceutically acceptable salt of any one of one or more claim 1-4 optionally with it is a kind of or many Plant purposes of the other therapeutic combination in the medicine for being used for suppressing RSV virus replications is prepared.
7. the purposes of claim 6, wherein RSV mutant of the virus from RSV viruses.
8. the compound or its pharmaceutically acceptable salt of any one of one or more claim 1-4 optionally with it is a kind of or many Plant purposes of the other therapeutic combination in the medicine for being used for preventing and/or treat rsv infection is prepared.
9. the purposes of claim 8, wherein mutant of the rsv infection from RSV viruses.
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